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  • richardmitnick 9:36 am on September 15, 2016 Permalink | Reply
    Tags: , How a New Drug Could Treat Both Diabetes and Bone Loss, , New compound SR10171, Scripps Institute, Type II diabetes and bone loss   

    From Scripps: “How a New Drug Could Treat Both Diabetes and Bone Loss” 

    Scripps
    Scripps Research Institute

    September 2016
    No writer credit

    In addition to its more obvious ills, type 2 diabetes is a condition closely associated with bone fractures – increasing the risk of fractures twofold. To make matters worse, certain anti-diabetic drugs further increase this risk, particularly in postmenopausal women, severely limiting their treatment options.

    But now, a team of scientists at on the Florida campus of The Scripps Research Institute (TSRI), co-led by TSRI’s Patrick R. Griffin and B. Lecka-Czernik, a professor at the University of Toledo, has shown that a new class of drug candidates developed at TSRI increase bone mass by expanding bone formation (deposition of new bone) and bone turnover (a normal process of bone replacement). The discovery could lead to new therapies for type 2 diabetes and bone loss. A proper balance of these two processes is critical to healthy bone maintenance, and this balance is frequently negatively affected in diabetic patients.

    The result is a new dual-targeting drug candidate – or, as Dr. Griffin describes it, “one drug addressing multiple therapeutic indications” – which could treat both diabetes and bone disease. The compound has been referenced as “SR10171.”

    Diabetes affects more than 29 million people in the United States, according to a 2012 report from the American Diabetes Association. In 2013, estimated direct medical costs of the disease totaled $176 billion.

    Over the past decade, Dr. Griffin and his colleague, TSRI Associate Professor Theodore Kamenecka, have focused on the details of molecules that increase sensitivity to insulin (a hormone that regulates blood sugar). Using newly discovered information, the researchers made significant advances in developing a family of drug candidates that target a receptor known as peroxisome proliferator-activated receptors gamma (PPARγ), a key regulator of stem cells controlling bone formation and bone resorption and a master regulator of fat.

    Anti-diabetic drugs known as glitazones (TZDs) target the PPARγ protein, but that interaction leads to severe bone loss and increased fractures. Stem cells in the bone marrow can differentiate either into bone cells or fat cells, and the glitazones drive them to fat at the expense of bone.

    But SR10171 is designed to avoid this troubling outcome. In animal models treated with the compound, fat formation in the bone marrow was successfully blocked independent of their metabolic state (healthy or diabetic).

    “Using structural biology techniques and rational design synthetic chemistry, SR10171 was constructed to engage the PPARγ protein in a unique way possessing an optimal balance with the receptor’s other family member, PPARa, to treat diabetes and, at the same time, improve bone health,” Dr. Griffin said. “This targeted polypharmacological approach demonstrates that the target isn’t the problem if you target it correctly.”

    The compound increases bone mass by protecting and increasing the activity of bone cells in various stages of normal bone maintenance, utilizing mechanisms that overlap those that regulate whole-body energy metabolism.

    “SR10171 improves bone mass regardless of body mass index, normal to obese,” Dr. Griffin added. “So you could use such a drug to treat osteoporosis whether patients are diabetic or not.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 1:26 pm on September 13, 2016 Permalink | Reply
    Tags: , , Scripps Institute, ,   

    From Scripps: “TSRI Scientists Discover Antibodies that Target Holes in HIV’s Defenses” 

    Scripps
    Scripps Research Institute

    September 12, 2016

    New Findings Could Lead to New AIDS Vaccine Candidates

    A new study from scientists at The Scripps Research Institute (TSRI) shows that “holes” in HIV’s defensive sugar shield could be important in designing an HIV vaccine.

    It appears that antibodies can target these holes, which are scattered in HIV’s protective sugar or “glycan” shield, and the question is now whether these holes can be exploited to induce protective antibodies.

    “It’s important now to evaluate future vaccine candidates to more rapidly understand the immune response they induce to particular glycan holes and learn from it,” said TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI.

    The study, published recently in the journal Cell Reports, was co-led by Burton, TSRI Associate Professor Andrew Ward, also of CHAVI-ID, and Rogier W. Sanders of the University of Amsterdam and Cornell University.

    A Clue to Stopping HIV

    Every virus has a signature structure, like the architecture of a building. By solving these structures, scientists can put together a blueprint showing where HIV is vulnerable to infection-blocking antibodies.

    In the 1990s, scientists discovered that HIV can have random holes in its protective outer shell of glycan molecules. Until now, however, scientists weren’t sure if antibodies could recognize and target these holes.

    Researchers at Cornell and TSRI had previously designed a stabilized version of an important HIV protein, called the envelope glycoprotein (Env) trimer, to prompt rabbit models to produce antibodies against the virus. In the new study, the plan was to reveal HIV’s vulnerabilities by examining where the antibodies bound the virus.

    “From work on HIV-positive individuals, we knew that the best way to understand an antibody response is to isolate the individual antibodies and study them in detail,” said Laura McCoy, a TSRI, IAVI and CHAVI-ID researcher now at University College London, who served as co-first author of the study with TSRI Senior Research Associate Gabriel Ozorowski, also of TSRI and CHAVI-ID, and Marit J. van Gils of the University of Amsterdam.

    To their surprise, when the researchers examined the rabbits’ antibodies, they found three rabbits had produced antibodies that targeted the same hole in Env. It appeared that antibodies could indeed target holes in the glycan shield.

    “This opened up a whole new concept,” said Ozorowski.

    If the immune system was targeting this hole—preferring it to other vulnerable spots on Env—maybe holes would be especially important in designing vaccine candidates.

    Toward Better Antibodies

    By analyzing the genetic sequences of thousands of strains of HIV, the researchers found that 89 percent of strains appear to have a targetable hole in the Env. The virus has a defense mechanism though—it quickly mutates to fill in these gaps.

    The researchers speculate that future vaccines might prompt the immune system to create antibodies to target holes. “Targeting a hole could help the immune system get its foot in the door,” Ozorowski said. Alternatively, the holes may prove a distraction and should be filled in so the immune system can focus on targeting better sites for neutralizing the virus.

    Burton said researchers must investigate the different possibilities, but he emphasized that this new understanding of glycan holes could help researchers narrow down the field of molecules needed in potential HIV vaccines.

    Ward added that this same method of “rational” vaccine design—where researchers use a virus’s precise molecular details to prompt the immune system to produce specific antibodies—can also be applied to efforts to fight other viruses, such as influenza and Ebola viruses.

    In addition to Burton, Ward, Sanders, McCoy, Ozorowski and van Gils, authors of the study, “Holes in the glycan shield of the native HIV envelope are a target of trimer-elicited neutralizing antibodies,” were Terrence Messmer, Bryan Briney, James E. Voss, Daniel W. Kulp, Devin Sok, Matthias Pauthner, Sergey Menis and Jessica Hsueh of TSRI, IAVI and CHAVI-ID; Christopher A. Cottrell, Jonathan L. Torres and Ian A. Wilson of TSRI and CHAVI-ID; Matthew S. Macauley of TSRI; and William R. Schief of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by CHAVI-ID (grant UM1AI100663), the National Institutes of Health’s HIV Vaccine Research and Design (HIVRAD) Program (grant P01 AI110657), the IAVI Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD, grants OPP1084519 and OPP1115782), a Marie-Curie Fellowship (FP7-PEOPLE-2013-IOF), the Aids Fonds Netherlands (grant 2012041), EMBO (grant ASTF260-2013), the Netherlands Organization for Scientific Research (grant 917.11.314) and the European Research Council (grant ERC-StG- 2011-280829-SHEV).

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG) From Scripps Research Institute.

    Scripps

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge

    BOINCLarge

    MyBOINC

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 12:39 pm on September 9, 2016 Permalink | Reply
    Tags: , , Scripps Institute, ,   

    From Scripps: “Team Harnesses Antibody Evolution on the Path to an AIDS Vaccine” 

    Scripps
    Scripps Research Institute

    September 12, 2016
    Madeline McCurry-Schmidt

    1
    The new work shows the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus. Shown here is the molecule eOD-GT8 60mer, used in the team’s reductionist strategy.

    A series of new studies led by scientists at The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) describe a potential vaccination strategy to jump-start the selection and evolution of broadly effective antibodies to prevent HIV infection. The researchers plan to test this strategy in an upcoming human clinical trial.

    The new studies, published September 8, 2016, in the journals Cell and Science, showed the immune system can be prompted to mimic and accelerate a rare natural process during which antibodies slowly evolve to become better and better at targeting the constantly mutating HIV virus.

    “Although we still have a long way to go, we’re making really good progress toward a human vaccine,” said William Schief, professor at TSRI and director of vaccine design for IAVI’s Neutralizing Antibody Center (NAC) at TSRI, whose lab developed many of the vaccine proteins tested in these studies.

    Schief co-led several of the new studies with TSRI Professor David Nemazee; Dennis Burton, James & Jessie Minor chair of the TSRI Department of Immunology and Microbial Science and scientific director of the IAVI NAC and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); and Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

    Developing a Blueprint

    A vaccine needs to elicit those rare antibodies, called “broadly neutralizing antibodies” (bnAbs), which fight a wide variety of strains of HIV—and it needs to elicit them quickly.

    One strategy to accomplish this, which scientists at TSRI have dubbed the “reductionist” strategy, is to find which antibody mutations are most important for making them effective against HIV, then to “prime” the immune system to start making antibody precursors. From there, scientists hope to prompt one important mutation after another with a series of different “booster” shots, deliberately building up a bnAb one step at a time.

    In a recent study in the journal PLOS Pathogens, the scientists created 3D maps of a structure on HIV known as the CD4 binding site. If antibodies successfully attack this site, scientists believe, most strains of HIV could be crippled. The researchers also created high-resolution maps of bnAbs that could bind to the CD4 binding site.

    “This is one of the most complete blueprints we’ve had for this target,” said Jean-Philippe Julien, a research associate in Wilson’s lab at the time of the study, who served as co-first author of the study with TSRI Research Associate Joseph Jardine, IAVI Research Scientist Devin Sok and Bryan Briney, assistant professor of immunology at TSRI.

    The scientists then studied stripped-down versions of the bnAbs to see exactly which components were important in targeting the CD4 binding site.

    With the results from the PLOS Pathogens study, the researchers finally had a guide to which mutations were the most important. They also had a better idea of which antibody-eliciting molecules, called immunogens, could be given in booster shots to trigger the right mutations at the right time.

    “We’re figuring how to boost antibodies to the next step—how to keep walking them along the path to increased breadth and potency after we get them started with a priming shot,” said Jardine.

    Training Promising Antibodies

    This finding set the stage for the three new studies. For the first one, published in Cell, researchers tested a priming immunogen, followed by a series of booster immunogens from the Schief lab. The immunogens were tested in a mouse model, developed by the Nemazee lab, which was engineered to have the genes (the raw materials) to make antibodies with the right mutations to target the CD4 binding site.

    The team found that the elicited antibodies more closely resembled mature antibodies. The sequence of immunogens had done their job.

    “The study showed that the immunogens are working,” said Nemazee. “They mutate the antibody-producing B cells in the right direction.”

    “The elicited antibodies share many genetic features with mature bnAbs and have the ability to neutralize one native HIV isolate as well as multiple other HIV isolates that we modified slightly to make them easier to neutralize,” added Briney, who served as first author of the study with Sok, Jardine, IAVI and TSRI Staff Scientist Daniel Kulp and TSRI Research Assistant Patrick Skog. “We will probably need additional booster immunogens to elicit antibodies that can broadly neutralize native HIV isolates, but our results suggest we are on the right track.”

    In the second Cell study, led by John R. Mascola at the NIH’s National Institute of Allergy and Infectious Disease (NIAID) Vaccine Research Center and Frederick W. Alt, a Howard Hughes Medical Institute (HHMI) researcher at Boston Children’s Hospital and Harvard Medical School, along with TSRI co-authors, took the reductionist approach a step further, showing that it could induce antibodies in mouse models with immune systems that can create an even wider range of antibodies—more similar to the human immune system.

    Results from the Science study further supported the reductionist vaccine approach. For the study, the researchers took on an even bigger challenge—to “prime” antibodies in a mouse model with a human-like immune system developed by Kymab Ltd, a UK-based company.

    The Kymab mouse model’s more complicated immune system made it more difficult for a vaccine protein to find and activate the “precursor” cells that have potential to produce bnAbs against the CD4 binding site. In fact, the researchers estimated that each Kymab mouse contained only one such precursor cell on average—with some mice containing none—among approximately 75 million antibody-producing cells.

    Despite this “needle-in-a-haystack” challenge, scientists found that their vaccine priming protein activated the appropriate antibody precursors in one-third to one-half of mice tested, suggesting this feat would also be possible in humans, where the targeted precursor cells are more plentiful. “This seems to be a much higher bar than we will face in humans,” Schief said.

    “The reductionist vaccine approach we’re undertaking will hopefully not only lead to an HIV vaccine, but also could potentially be applied to other challenging vaccine targets,” said Sok, who served as co-first author of the Science study with Briney, Jardine and Kulp.

    The researchers also gave credit to their strong international collaboration. “Our phenomenal results with the team at The Scripps Research Institute came from work at the interfaces—and boundaries—of vaccine technology, immunology, protein engineering and structural biology,” said Professor Allan Bradley, chief technical officer at Kymab and director emeritus of the Wellcome Trust Sanger Institute.

    IAVI and partners are planning for a clinical trial for next year to further develop and test whether the reductionist vaccine strategy—starting with activating the right precursors—will work in humans. If successful, the next step will be to test their booster immunogens.

    The first Cell study, Tailored Immunogens Direct Affinity Maturation Toward HIV Neutralizing Antibodies, included additional authors from the Ragon Institute. The study was supported by the IAVI through the NAC (grant SFP1849); NIAID grants; CHAVI-ID (grants UM1AI100663, P01AI081625 and R01AI073148); the Ragon Institute; and the Helen Hay Whitney Foundation.

    The second Cell study, Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires, included additional authors from HHMI; Boston Children’s Hospital; Harvard Medical School; the NIH’s NIAID Vaccine Research Center; Vanderbilt University; Columbia University; the Ragon Institute; Fred Hutchinson Cancer Center and the Duke University School of Medicine. This work was supported by the NIH (grants R01AI077595, AI020047, P01 AI094419, U19AI109632, P01-AI104722; CHAVI-ID (grants 5UM1 AI100645 and 1UM1 AI100663); the intramural research program of the NIAID Vaccine Research Center; the IAVI NAC Center; Collaboration for AIDS Vaccine Discovery funding for the IAVI NAC Center; the Ragon Institute and an HHMI Medical Student Fellowship.

    The Science study, Priming HIV-1 Broadly Neutralizing Antibody Precursors in Human Ig Loci Transgenic Mice, included additional authors from Kymab Ltd, the Wellcome Trust Sanger Institute and the Ragon Institute. The study was supported by IAVI, with the generous support of the United States Agency for International Development (USAID); Ministry of Foreign Affairs of the Netherlands; the Bill & Melinda Gates Foundation; the Ragon Institute; the Helen Hay Whitney Foundation; and NIAID (grants P01 AI094419 and CHAVI-ID 1UM1AI100663).

    See also additional Cell and Immunity studies on HIV/AIDS vaccine work led by TSRI scientists and published on September 8.

    See the full article here .

    YOU CAN HELP IN THE FIGHT AGAINST HIV/AIDS FROM THE COMFORT OF YOUR EASY CHAIR.

    The Fight AIDS at home (FAAH@home) Phase II project is now running at World Community Grid (WCG)

    FAAH Phase II

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the FAAH@home Phase II project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 11:03 am on August 23, 2016 Permalink | Reply
    Tags: , , , Scripps Institute   

    From Scripps: “A Look Deep Inside the Human Brain Reveals a Surprise” 

    Scripps
    Scripps Research Institute

    8.23.16
    No writer credit

    In the field of neuroscience, researchers often make the assumption that information they obtain from a tiny brain sample is true for the entire brain.

    Now, a team of scientists at The Scripps Research Institute (TSRI), University of California, San Diego (UC San Diego) and Illumina, Inc., has completed the first large-scale assessment of the way thousands of single neuronal nuclei produce proteins from genetic information (“transcription”) – revealing a surprising diversity in the process. The findings could improve both our understanding of the brain’s normal functioning and how it’s damaged by diseases such as Alzheimer’s, Parkinson’s, ALS and depression.

    [The study is published in Science.]

    The researchers accomplished this feat by isolating and analyzing 3,200 single human neurons, more than 10-fold greater than prior publications, from six Brodmann Areas (larger regions having functional roles) of the human brain.

    “Through a wonderful scientific collaboration, we found an enormous amount of transcriptomic diversity from cell to cell that will be relevant to understanding the normal brain and its diseases such as Alzheimer’s, Parkinson’s, ALS and depression,” said TSRI Professor and neuroscientist Jerold Chun, who co-led the study with bioengineers Kun Zhang and Wei Wang of UC San Diego and Jian-Bing Fan of Illumina.

    While parts of the cerebral cortex look different under a microscope – with different cell shapes and densities that form cortical layers and larger regions having functional roles called “Brodmann Areas” – most researchers treat neurons as a fairly uniform group in their studies. “From a tiny brain sample, researchers often make assumptions that obtained information is true for the entire brain,” said Dr. Chun.

    But the brain isn’t like other organs, Dr. Chun explained. There’s a growing understanding that individual brain cells are unique, and a possibility has been that the microscopic differences among cerebral cortical areas may also reflect unique transcriptomic differences – i.e., differences in the expressed genes, or messenger RNAs (mRNAs), which carry copies of the DNA code outside the nucleus and determine which proteins the cell makes.

    With the help of newly developed tools to isolate and sequence individual cell nuclei (where genetic material is housed in a cell), the researchers deciphered the minute quantities of mRNA within each nucleus, revealing that various combinations of the 16 subtypes tended to cluster in cortical layers and Brodmann Areas, helping explain why these regions look and function differently.

    Neurons exhibited anticipated similarities, yet also many differences in their transcriptomic profiles, revealing single neurons with shared, as well as unique, characteristics that likely lead to differences in cellular function.

    “Now we can actually point to an enormous amount of molecular heterogeneity in single neurons of the brain,” said Gwendolyn E. Kaeser, a UC San Diego Biomedical Sciences Graduate Program student studying in Dr. Chun’s lab at TSRI and co-first author of the study.

    Interestingly, some of these differences in gene expression have roots in very early brain development taking place before birth. The researchers found markers on some neurons showing that they originated from a specific region of fetal brain called the ganglionic eminence, which generates inhibitory neurons destined for the cerebral cortex. These neurons may have particular relevance to developmental brain disorders.

    In future studies, the researchers hope to investigate how single-neuron DNA and mRNA differ in single neurons, groups and between human brains – and how these may be influenced by factors such as stress, medications or disease.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 12:21 pm on August 18, 2016 Permalink | Reply
    Tags: , , Scripps Institute, TSRI Scientists Find Potential Treatment for 'Painful Blindness' Form of Dry Eye   

    From Scripps: “TSRI Scientists Find Potential Treatment for ‘Painful Blindness’ Form of Dry Eye” 

    Scripps
    Scripps Research Institute

    August 18, 2016
    No writer credit

    1
    The Scripps Research Institute team found “progenitor” cells isolated from healthy lacrimal glands can improve the appearance and function of diseased tissue. (Image courtesy of TSRI’s Makarenkova lab.)

    The eye’s lacrimal gland is small but mighty. This gland produces moisture needed to heal eye injuries and clear out harmful dust, bacteria and other invaders.

    If the lacrimal gland is injured or damaged by aging, pollution or even certain pharmaceutical drugs, a person can experience a debilitating condition called aqueous deficiency dry eye (ADDE)—sometimes called “painful blindness.”

    Now a new study in animal models, led by scientists at The Scripps Research Institute (TSRI), suggests that lacrimal glands can be repaired by injecting a kind of regenerative “progenitor” cell.

    “This is the first step in developing future therapies for the lacrimal gland,” said TSRI biologist Helen Makarenkova, who led the study.

    The findings were published this week in the online Early Edition of the journal Stem Cells Translational Medicine.

    Up for the Challenge

    If injured, a healthy lacrimal gland naturally regenerates itself in about seven days. When diseased and chronically inflamed, however, regeneration stops—and scientists are not sure why.

    In the new study, Makarenkova and her colleagues looked at whether they could kick start regeneration by injecting progenitor cells into the lobes that make up the lacrimal gland. Progenitor cells are similar to stem cells in their ability to differentiate into different kinds of tissue. In this study, the researchers used progenitor cells that were poised to become epithelial tissue, a key component of the lacrimal gland.

    The researchers knew they faced a major challenge: sorting and separating “sticky” epithelial cell progenitors without destroying them.

    “We had to figure out how to dissociate the tissue into single cells without completely obliterating everything,” said Anastasia Gromova, the study’s first author, now a graduate student at the University of California, San Diego, who spearheaded the project while interning at TSRI during her undergraduate years.

    The researchers solved this problem by developing markers to label the cells of interest and then testing different enzymes and other reagents to draw them out of tissues.

    Restoring Eye Health

    With these cells in hand, the researchers injected them into the lacrimal glands of mouse models of Sjogren’s syndrome, an autoimmune disease that results in ADDE, dry mouth and other symptoms. The team used only older, female mice because ADDE most commonly strikes that demographic in humans.

    The treated mice showed a significant increase in tear production, indicating—for the first time—that epithelial cell progenitors could repair the lacrimal gland. Further tests suggested that epithelial cell progenitors helped by restoring the connection between cells called myoepithelial contractile cells and the lacrimal gland’s secretory cells, which produce tears.

    The next step in this research will be to study how long the improvement in the lacrimal gland lasts after progenitor cell injections. Makarenkova said the eventual goal is to develop therapies to boost a patient’s own regenerative abilities.

    In addition to Makarenkova and Gromova, authors of the study, “Lacrimal Gland Repair Using Progenitor Cells,” were Dmitry A. Voronov of TSRI, the Russian Academy of Sciences and the A.N. Belozersky Institute of Physico-Chemical Biology of the Lomonosov Moscow State University; Miya Yoshida and Suharika Thotakura of TSRI; Robyn Meech of Flinders University; and Darlene A. Dartt of the Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School.

    The research was supported by the National Institutes of Health’s National Eye Institute (grant EY021292), the Russian Foundation for Basic Research (grant 12-04-01621-a) and an Australian Research Council (ARC) Future Fellowship.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 1:27 pm on August 16, 2016 Permalink | Reply
    Tags: , Primordial ‘RNA World’, Scripps Institute   

    From Scripps: “TSRI Scientists Take Big Step Toward Recreating Primordial ‘RNA World’ of Four Billion Years Ago” 

    Scripps
    Scripps Research Institute

    August 15, 2016

    Scientists at The Scripps Research Institute (TSRI) have taken a big step toward the laboratory re-creation of the “RNA world,” which is generally believed to have preceded modern life forms based on DNA and proteins.

    “This is probably the first time some of these complex RNA molecules have been synthesized with a ribozyme [a special RNA enzyme] since the end of the RNA world four billion years ago,” said TSRI Professor Gerald F. Joyce, the senior author of the study.

    The results from the study, reported this week in the online Early Edition of the Proceedings of the National Academy of Sciences, show the scientists have succeeded in creating a ribozyme that can basically serve both to amplify genetic information and to generate functional molecules.

    The new ribozyme can replicate short lengths of RNA efficiently and perform transcription on even longer RNAs to make functional RNA molecules with complex structures—coming close to what scientists imagine in terms of an RNA replicator that could have supported life before modern biology, where protein enzymes now handle gene replication and transcription.

    Taking Up a Decades-Old Challenge

    In the new study, Joyce and TSRI Research Associate David P. Horning set out to use test-tube evolution techniques to tackle the decades-old challenge of creating an enzyme that could both replicate and transcribe RNA and thus support an RNA world.

    The team started with an enzyme that had been developed and improved upon by other researchers since the early 1990s. The class I RNA polymerase ribozyme, as it has come to be known, can perform the basic task of RNA synthesis—required for transcribing an RNA template into a functional RNA molecule—by binding to a strand of RNA and using it as a template to stitch together a complementary RNA strand.

    But prior forms of the ribozyme had been very limited in the RNA sequences they could handle, and couldn’t transcribe RNAs that have even moderately complex structures. Because of those limitations, they also could not perform full replication of RNA, which requires the transcription of a complementary strand back into a copy of the original.

    Horning and Joyce drew upon several improvements described in previous research and then added random mutations to create a population of roughly 100 trillion distinct variants of the molecule. Mimicking the evolutionary process of natural selection, they set up a system to isolate only the variant ribozymes that could synthesize—from the respective RNA templates—two different and challenging RNA molecules, which have mixed sequences and complex structures, and have functions in the sense that they bind tightly to specific target molecules.

    “The selection was based on the ability of these newly synthesized RNAs to actually function by binding to their targets,” said Horning. “To be able to make these functional RNAs, the ribozyme effectively had to evolve to become versatile in terms of the sequence and the structure of the RNA it could handle.”

    Best Performer

    The best performer after two dozen rounds of selection, polymerase ribozyme 24-3, proved capable of synthesizing not only the two target-binding RNAs but also several other structurally complex RNA molecules that exist in nature—as functional remnants of the ancient RNA world—including a yeast version of a “transfer RNA” molecule that has an essential protein-making role in all cells.

    “We found that the new ribozyme can handle most sequences and all but the most difficult structures, so we can use it to make a variety of functional RNA molecules,” Joyce said.

    Even when synthesizing the limited RNA sequences that the original class I RNA polymerase ribozyme could handle, ribozyme 24-3 proved capable of stitching them together about 100 times faster than its ancestor could.

    Turning to the much harder task of replication, the TSRI researchers found that ribozyme 24-3 could copy RNAs of up to two dozen nucleotides, achieving what biologists call “exponential replication” and creating as many as 40,000 copies of a target RNA within 24 hours.

    The 24-3 ribozyme is thus the first ever to combine the two basic capabilities—RNA synthesis and RNA replication—necessary for a pre-protein, pre-DNA world of RNA life.

    To generate and sustain a true “RNA world,” the new ribozyme will have to be improved further to enable the replication of longer, more complex RNA molecules—crucially including the polymerase ribozyme itself. The Joyce laboratory is now driving its ribozyme toward that goal with further test-tube evolution experiments.

    “A polymerase ribozyme that achieves exponential amplification of itself will meet the criteria for being alive,” Joyce said. “That’s a summit that’s now within sight.”

    Funding for the study, “Amplification of RNA by an RNA polymerase ribozyme,” was provided by the National Aeronautics and Space Administration (NNX14AK15G) and the Simons Foundation (287624).

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 3:25 pm on August 12, 2016 Permalink | Reply
    Tags: , , , , Scripps Institute   

    From Scripps: “Team Pinpoints Ebola’s Weak Spots” 

    Scripps
    Scripps Research Institute

    8.12.16
    Madeline McCurry-Schmidt

    Scientists at The Scripps Research Institute (TSRI) now have a high-resolution view of exactly how the experimental therapy ZMapp™ targets Ebola virus.

    The new study is also the first to show how an antibody in the ZMapp™ “drug cocktail” targets a second Ebola virus protein, called sGP, whose vulnerable spots had previously been unknown.

    “This sGP protein is tremendously important,” said TSRI Professor Erica Ollmann Saphire, who co-led the study with TSRI Associate Professor Andrew Ward. “This is the roadmap we need to target the right molecules in infection.”

    “Determining the proper balance in targeting these two Ebola proteins will be key to building improved therapeutics,” added Ward.

    The study was published August 8, 2016 in the journal Nature Microbiology.

    1
    The team succeeded in showing how experimental therapy ZMapp™ targets the Ebola virus, here pictured targeting the virus’s GP protein. (Image courtesy of Andrew Ward and Jesper Pallesen.)

    Zooming in on ZMapp™

    Scientists need detailed images of Ebola virus’s molecular structure. Like enemy reconnaissance, structures can show where Ebola is vulnerable and how medical treatments can neutralize it.

    TSRI scientists are harnessing an imaging technique called cryo-electron microscopy (in which a sample is pelted with electrons) to create high-resolution, 3-D images of Ebola virus and the antibodies that fight it.

    “We’re at the cutting edge of our ability to resolve high-resolution protein complexes,” said TSRI Research Associate C. Daniel Murin, co-first author of the new study with TSRI Research Associate Jesper Pallesen.

    In the new study, the researchers used cryo-electron microscopy to see exactly how Ebola virus interacts with the three antibodies in the ZMapp™ experimental therapy produced by Mapp Biopharmaceutical, also a study collaborator.

    The researchers had imaged these interactions at a low resolution in a 2014 study, but the new study revealed substantially more details, including the exact angles the antibodies use to approach the molecule on the surface of the virus, termed its surface glycoprotein (GP), and the individual amino acid contact points at which the antibodies bind GP. This information provides new clues to researchers trying to make the antibodies even more effective.

    “The three components of ZMapp™, now resolved at high-resolution, can be further engineered in a structure-based manner for improved potency,” said Ward.

    Solving an Elusive Structure

    Next, the researchers took a closer look at one of the three antibodies that make up ZMapp™, called 13C6. This antibody is unique because it can also target the soluble Ebola protein sGP.

    sGP’s role in infection is a mystery. Ebola virus makes the protein profusely, indicating that it is important, but then sGP appears just to float in a person’s blood serum. One theory is that sGP may be essential in the natural host “reservoir.”

    “Eighty to ninety percent of what Ebola virus makes in infection is this shed molecule,” said Saphire. “It’s like a smoke screen, and we need to know where it is similar to our target GP and where it is different.”

    To add to the mystery, Ebola makes GP and sGP using the same gene. A small difference in the way the gene is read changes how the molecules are shaped and changes their roles.

    One obstacle to understanding sGP is that it is too small to be seen with cryo-electron microscopes. To solve this problem, the researchers added “bulk” by pairing sGP with antibodies, including 13C6. This allowed them to kill two birds with one stone—they could see sGP’s structure while also studying how antibodies interact with it.

    The new image shows the binding sites, or “epitopes,” the antibody targets. “We can see hot spots on this virus that we can hit,” said Pallesen.

    This study is the latest research from the Viral Hemorrhagic Fever Consortium, an international partnership of research institutes led by Saphire. The researchers said collaboration with the consortium was key to this study, allowing scientists to share samples and data, including viral genetic sequences isolated from patients in the most recent Ebola outbreak.

    In addition to Saphire, Ward, Murin and Pallesen, authors of the study, Structures of Ebola virus GP and sGP in complex with therapeutic antibodies, were Natalia de Val, Christopher A. Cottrell, Kathryn M. Hastie, Hannah Turner and Marnie Fusco of TSRI; Kristian G. Andersen of TSRI and the Scripps Translational Science Institute; Andrew I. Flyak and James E. Crowe of Vanderbilt University and Larry Zeitlin of Mapp Biopharmaceutical.

    This study was supported by the National Institutes of Health (NIH, grant R01 AI067927), the NIH’s National Institute of Allergy and Infectious Diseases (grants U19AI109762 and U19AI109711) and the National Science Foundation.

    See the full article here .

    You can Help Stamp Out EBOLA.

    This WCG project rubs at Scripps Institute

    Outsmart Ebola Together

    You can help researchers at The Scripps Research Institute find a cure for Ebola by donating your computing power to this project and encouraging others to join.

    Visit World Community Grid (WCG). Download and install the BOINC software on which it runs. Attach to the Outsmart Ebola Together project. This will allow WCG to use your computer’s free CPU cycles to process computational data for the project.

    WCGLarge
    WCG Logo New

    BOINCLarge
    BOINC WallPaper

    While you are at WCG and BOINC, check out the other very worthwhile projects running on this software. All project results are “open source”, free for the use of scientists world while to advance health and other issues of mankind.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 11:39 am on August 12, 2016 Permalink | Reply
    Tags: , , New Study Shines Light on Mutations Responsible for Debilitating Heart Conditions, Scripps Institute   

    From Scripps: “New Study Shines Light on Mutations Responsible for Debilitating Heart Conditions” 

    Scripps
    Scripps Research Institute

    August 11, 2016

    1
    Binding to the plasma membrane induces metavinculin dimerization which stabilizes cardiac adhesion sites. The metavinculin mutation causing the most severe cardiomyopathy prevents metavinculin dimerization. The lipids are shown as spheres and the metavinculin tail domain as a cartoon with the 5 alpha-helices (H1-H5) of the 5-helix bundle colored spectrally (H1, red; H2, orange; H3, yellow; H4, green; H5, blue). (Image courtesy of the Izard lab.)

    The leading cause of death in the world remains cardiovascular diseases, which are responsible for more than one third of overall mortality, according to the World Health Organization. Obesity and diet are obvious culprits behind heart disease but, over the past decade, research has also pointed to genetic factors, specifically mutations in cell adhesion components—the forces that bind cells together.

    In a new study, scientists from the Florida campus of The Scripps Research Institute offer new molecular insights into how the interaction between specific genetic mutations and a cytoskeletal protein critical for the proper development and maintenance of heart tissue can lead to conditions such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM)—and ultimately heart failure.

    The new study, which was led by Associate Professor T. Izard of the Florida campus of TSRI, is published this week in an early online edition of the journal Proceedings of the National Academy of Sciences. The new insights could aid in the development of drug therapies to strengthen the hearts of patients suffering from age-related heart failure.

    The study focuses on the protein vinculin and a variant form known as metavinculin, which is found only in muscle tissue. Vinculin has been shown to reinforce the myocardial cell cytoskeleton, improving heart muscle contractility and prolonging life, while metavinculin plays an essential role in the development and function of the heart.

    Both vinculin and metavinculin regulate cell adhesion and migration by linking the cell’s cytoskeleton to adhesion receptor complexes via a process known as dimerization—the joining of two similar subunits. Control of the dimerization process is crucial for normal protein function in cell adhesion sites.

    But mutations in the variant metavinculin, either inherited or spontaneous, corrupt this process, altering dimerization and, the study suggests, producing a decreased ability to stabilize critical cell adhesions, weakening the heart muscle over time.

    The first author of the study, Differential Lipid Binding of Vinculin Isoforms Promotes Quasiequivalent Dimerization, is Krishna Chinthalapudi of TSRI. Other authors include Erumbi S. Rangarajan of TSRI and David T. Brown of the University of Mississippi Medical Center.

    The laboratory is supported by the National Institutes of Health, the Department of Defense, the American Heart Association and the State of Florida.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 5:15 pm on August 1, 2016 Permalink | Reply
    Tags: , , Scripps Institute, TSRI Study Points Way to Better Vaccines and New Autoimmune Therapies   

    From Scripps: “Found: A Potential New Way to Sway the Immune System” 

    Scripps
    Scripps Research Institute

    August 1, 2016
    No writer credit found

    TSRI Study Points Way to Better Vaccines and New Autoimmune Therapies

    A new international collaboration involving scientists at The Scripps Research Institute (TSRI) opens a door to influencing the immune system, which would be useful to boost the effectiveness of vaccines or to counter autoimmune diseases such as lupus and rheumatoid arthritis.

    The research, published August 1, 2016, in The Journal of Experimental Medicine, focused on a molecule called microRNA-155 (miR-155), a key player in the immune system’s production of disease-fighting antibodies.

    “It’s very exciting to see exactly how this molecule works in the body,” said TSRI Associate Professor Changchun Xiao, who co-led the study with Professor Wen-Hsien Liu of Xiamen University in Fuijan province, China.

    An Immune System Tango

    Our cells rely on molecules called microRNAs (miRNAs) as a sort of “dimmer switches” to carefully regulate protein levels and combat disease.

    “People know miRNAs are involved in immune response, but they don’t know which miRNAs and how exactly,” explained TSRI Research Associate Zhe Huang, study co-first author with Liu and Seung Goo Kang of TSRI and Kangwon National University.

    In the new study, the researchers focused on the roles of miRNAs during the critical period when the immune system first detects “invaders” such as viruses or bacteria. At this time, cells called T follicular helpers proliferate and migrate to a different area of the lymph organs to interact with B cells.

    “They do a sort of tango,” said Xiao.

    This interaction prompts B cells to mature and produce effective antibodies, eventually offering long-term protection against infection.

    “The next time you encounter that virus, for example, the body can respond quickly,” said Xiao.

    Identifying a Dancer

    Using a technique called deep sequencing, the team identified miR-155 as a potential part of this process. Studies in mouse models suggested that miR-155 works by repressing a protein called Peli1. This leaves a molecule called c-Rel free to jump in and promote normal T cell proliferation.

    This finding could help scientists improve current vaccines. While vaccines are life-saving, some vaccines wear off after a decade or only cover around 80 percent of those vaccinated.

    “If you could increase T cell proliferation using a molecule that mimics miR-155, maybe you could boost that to 90 to 95 percent,” said Xiao. He also sees potential for using miR-155 to help in creating longer-lasting vaccines.

    The research may also apply to treating autoimmune diseases, which occur when antibodies mistakenly attack the body’s own tissues. Xiao and his colleagues think an mRNA inhibitor could dial back miR-155’s response when T cell proliferation and antibody production is in overdrive.

    For the next stage of this research, Xiao plans to collaborate with scientists on the Florida campus of TSRI to test possible miRNA inhibitors against autoimmune disease.

    In addition to Xiao, Huang, Liu and Kang, authors of the study, “A miR-155-Peli1-c-Rel pathway controls the generation and function of T follicular helper cells,” were Cheng-Jang Wu and Li-Fan Lu of the University of California, San Diego; Yi Liu and Alexander Hoffmann of the University of California, Los Angeles; Shunbin Xu of Wayne State University; Guo Fu and Nengming Xiao of Xiamen University; Ye Zheng of The Salk Institute for Biological Studies; and Hyun Yong Jin, Christian J. Maine, Jovan Shepherd, Mohsen Sabouri-Ghomi and Alicia Gonzalez-Martin of TSRI.

    The study was supported by the PEW Charitable Trusts; Cancer Research Institute; Lupus Research Institute; National Institutes of Health (grants R01AI087634, R01AI089854, R56AI110403, R56AI121155, R01AI103646 and R01AI108651); National Natural Science Foundation of China (grants 31570882, 31570883 and 31570911); 1000 Young Talents Program of China (grant K08008); the Fundamental Research Funds for the Central Universities of the People’s Republic of China (grant 20720150065); Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (grant NRF-2015R1C1A1A01052387, S.G.K.) and a 2016 Research Grant from Kangwon National University.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 9:05 am on July 28, 2016 Permalink | Reply
    Tags: , Scripps Institute, SR10171, Type 2 diabetes   

    From Scripps: “Study Suggests New Drug Candidate Could Treat Both Type 2 Diabetes and Bone Loss” 

    Scripps
    Scripps Research Institute

    July 27, 2016

    In addition to its more obvious ills, type 2 diabetes is a condition closely associated with bone fractures, increasing the risk of fractures twofold. To make matters worse, certain anti-diabetic drugs further increase this risk, particularly in postmenopausal women, severely limiting their treatment options.

    A new study, co-led by Patrick R. Griffin, a professor on the Florida campus of The Scripps Research Institute (TSRI), and B. Lecka-Czernik, a professor at the University of Toledo, has shown that a new class of drug candidates developed at TSRI increases bone mass by expanding bone formation (deposition of new bone) and bone turnover (a normal process of replacement of old bone). A proper balance of these two processes is critical to healthy bone maintanence, and this balance is frequently negatively affected in diabetic patients.

    The result is a new dual-targeting drug candidate—or, as Griffin describes, “one drug addressing multiple therapeutic indications”—that could treat both diabetes and bone disease. The compound has been referenced as “SR10171.”

    The study was published recently online ahead of print by the journal EBioMedicine.

    Diabetes affects more than 29 million people in the United States, according to a 2012 report from the American Diabetes Association. Between 2010 and 2012, the incidence rate was about 1.7 to 1.9 million per year, and in 2013, estimated direct medical costs of the disease were $176 billion.

    Over the past decade, Griffin and his colleague, TSRI Associate Professor Theodore Kamenecka, have focused on the details of molecules that increase sensitivity to insulin (a hormone that regulates blood sugar). Using newly discovered information, the researchers made significant advances in developing a family of drug candidates that target a receptor known as peroxisome proliferator-activated receptors gamma (PPARγ), a key regulator of stem cells controlling bone formation and bone resorption and a master regulator of fat.

    Anti-diabetic drugs known as glitazones (TZDs) target the PPARγ protein, but that interaction leads to severe bone loss and increased fractures. Stem cells in the bone marrow can differentiate either into bone cells or fat cells, and the glitazones drive them to fat at the expense of bone.

    But SR10171 is designed to avoid this troubling outcome. In animal models treated with the compound, fat formation in the bone marrow was successfully blocked independent of their metabolic state (healthy or diabetic).

    “Using structural biology technigues and rational design synthetic chemistry, SR10171 was constructed to engage the PPARγ protein in a unique way possessing an optimal balance with the receptor’s other family member, PPARa, to treat diabetes and, at the same time, improve bone health,” Griffin said. “This targeted polypharmacological approach demonstrates that the target isn’t the problem if you target it correctly.”

    The compound increases bone mass by protecting and increasing the activity of bone cells in various stages of normal bone mantanence, utilizing mechanisms that overlap those that regulate whole-body energy metabolism.

    “SR10171 improves bone mass regardless of body mass index, normal to obese,” Griffin added. “So you could use such a drug to treat osteoporosis whether patients are diabetic or not.”

    The first author of the study, PPARG Post-Translational Modifications Regulate Bone Formation and Bone Resorption, is L.A. Stechschulte of the University of Toledo, Ohio. Other authors include P.J. Czernik, Z.C. Rotter and F.N. Tausif of the University of Toledo; C.A. Corzo, D.P. Marciano, A. Asteian, J. Zheng and T.M. Kamenecka of TSRI; J. B. Bruning of The University of Adelaide, Australia; and C.J. Rosen of the Maine Medical Center Research Institute.

    The study was supported by the National Institutes of Health (grant numbers DK080261 and DK105825); the American Diabetes Association (award 7-13-BS-089), the Abrams Charitable Trust and the Klorfine Family Fellowship.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
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