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  • 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.

     
  • richardmitnick 9:39 am on July 14, 2016 Permalink | Reply
    Tags: , , Scripps Institute   

    From Scripps: “Catching Cancer-Causing Mutations in the Act” 

    Scripps
    Scripps Research Institute

    July 2016
    No writer credit found

    Cancer can be caused by mutations in cell DNA, and researchers at The Scripps Research Institute (TSRI) have discovered how one mutation, in a protein known as POT1, causes some of the most aggressive forms of cancer, including leukemia, lymphoma, glioma and melanoma. The research also suggests a possible way to kill these kinds of tumors by targeting an important enzyme.

    1
    Eros Lazzerini Denchi of The Scripps Research Institute co-led the study with Agnel Sfeir of New York University School of Medicine.

    “We’ve found the mechanism through which this mutation leads to a scrambling of the genome,” said TSRI Associate Professor Eros Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York University (NYU) School of Medicine. “That’s when you get really massive tumors.”

    The researchers investigated mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.

    POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme called ATR that triggers programmed cell death.

    Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukemia and melanoma.

    “Somehow those cells found a way to survive – and thrive,” said Dr. Lazzerini Denchi. “We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

    Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.

    “The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” said Dr. Lazzerini Denchi.

    P53, a well-known tumor suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumors. The findings led the team to consider a new strategy for killing these tumors.

    Scientists know that all cells – even cancer cells – will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumors without affecting healthy cells. “This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” said Dr. Lazzerini Denchi.

    The researchers plan to investigate this new therapeutic approach in future studies.

    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 1:52 pm on July 1, 2016 Permalink | Reply
    Tags: , , Scripps Institute   

    From Scripps: “Researchers Stabilize HIV Structure, Design Potential AIDS Vaccine Candidates” 

    Scripps
    Scripps Research Institute

    July 04, 2016
    Madeline McCurry-Schmidt

    Want to catch a criminal? Show a mugshot on the news.

    Want to stop HIV infections? Get the immune system to recognize and attack the virus’s tell-tale structure.

    1
    “We’ve figured out one of the fundamental reasons why HIV is metastable,” says Assistant Professor Jiang Zhu (left), here with some co-authors of the new studies, Charles Morris (back), Parisa Azadnia (center) and Linling He. (Photo by Cindy Brauer.)

    2
    In a feat of bioengineering, the team designed nanoparticles that could mimic HIV.

    That’s part of the basic approach behind efforts at The Scripps Research Institute (TSRI) to design an AIDS vaccine. This strategy may hinge on finding new ways to stabilize proteins called HIV-1 surface antigens and in designing HIV-like particles to prompt the body to fight the real virus.

    Now two new studies led by TSRI scientists advance these efforts. The first describes a strategy to stabilize an important HIV structure and potentially create HIV lookalikes for large-scale vaccine production. The second study engineers novel nanoparticles as vaccine candidates, using this new knowledge.

    “This is a big accomplishment in terms of engineering and design,” said TSRI biologist Jiang Zhu.

    Zhu co-led the first study with Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI, and co-led the second with TSRI Associate Professor Andrew Ward.

    The findings were published June 28, 2016 in the journal Nature Communications.

    Stabilizing HIV

    In the first publication, Zhu and researcher Leo Kong (a study first author now at the National Institutes of Health) built on previous structural studies from the Ward and Wilson labs to investigate a trait called “metastability.” Metastability describes the tense state of the HIV Envelope glycoprotein (Env) trimer when it is poised like a loaded spring to undergo the dramatic changes that allow the virus to enter cells.

    Metastability poses a problem for scientists who want to create a precise image of this viral target and see what the human immune system is up against.

    Metastability also stands in the way of naturally occurring immunity and vaccine production. For the adaptive immune system to work in either case, it needs to recognize a functional, stable version of a virus’s proteins—a sort of mugshot—so it can produce antibodies and attack the actual virus upon encountering it.

    Unfortunately, because of the virus’s metastability, or shape-shifting tendency, structures of HIV’s proteins have proven difficult to establish for use in vaccine design. The Ward and Wilson groups at TSRI have previously determined cryo-EM and x-ray structures for other Env constructs; however, current methods to stabilize Env in one strain of HIV won’t necessarily stabilize it in another, making it hard to design an arsenal of Env proteins to help elicit “broadly neutralizing antibodies” that could fight many types of HIV.

    To advance the vaccine effort, TSRI researchers wanted to track down the root cause of metastability, and Jiang and Kong hypothesized that altering a key region of Env would improve its overall properties.

    They hypothesized that a region of the Env called HR1 could be linked to metastability.

    “The HR1 basically resembles a highly bent twig that is ready to spring back straight,” said Kong. “This small bend in the HR1 region is likely ground zero for metastability. In most published Env structures, this region appears disordered when mutated or loosely packed when in its native form. From these observations, it seemed reasonable that rewiring the HR1 bend could greatly stabilize Env.”

    Indeed, when the scientists tweaked HIV’s genetic sequence, they were able to shorten the HR1 region, preventing its transformation and keeping the rest of the structure stable.

    “We’ve figured out one of the fundamental reasons why HIV is metastable,” said Zhu.

    The researchers then demonstrated that their stabilized Env trimers also almost perfectly mimicked the structure of the real HIV trimer, suggesting they could be useful in vaccines. Since rewiring the HR1 should prevent Env undergoing its necessary shape-shifting changes to infect cells, the stabilization strategy also could lead to protein or DNA-based vaccines. Furthermore, the modified trimer also has the potential to be produced in reasonably large quantities and at high purity—important considerations in industrial-scale vaccine production.

    Finally, since many viruses contain metastable Env proteins with HR1-like regions, this TSRI-developed engineering approach may be applicable in the design of vaccines against other viral pathogens such as influenza and Ebola virus.

    New Vaccine Candidates

    In the second paper, the researchers looked into designing nanoparticles that could mimic HIV.

    Particles aren’t new in vaccine design. They provide the backbone of successful vaccines against human papillomavirus (HPV), hepatitis B and hepatitis E—“the most efficacious human vaccines ever made,” according to Zhu.

    These nanoparticles are called virus-like particles (VLPs) and are hollow shells of other proteins found in nature. Scientists have found that they can add viral proteins to the outside of a shell, creating a phony virus. The imposter then prompts the body to produce antibodies for long-term protection against the real virus.

    But as Zhu and his colleagues focused on creating HIV-like VLPs, the Env trimer, once again, presented a challenge.

    The trimer is made of three subunits that come together to form a base with a crown shape on top. The top of the crown is where the tips of the three subunits meet.

    Scientists have found that the immune system cannot produce broadly neutralizing antibodies when a vaccine contains only one part of the trimer. The immune system needs to see intact HIV proteins—also called antigens when they stimulate the immune system to create antibodies—in their native trimeric context.

    To construct an artificial virus, in the new study the researchers added HIV trimers to nanoparticles that naturally lock their own subunits together in clusters of three. As the three subunits come together, the researchers hypothesized, they could bring the HIV antigens together to form a trimer.

    “Our idea was to ‘fuse’ a trimeric HIV-1 antigen to a nanoparticle subunit, so when the subunits ‘self-assemble’ they bring three attached HIV-1 antigens together,” said TSRI Staff Scientist Linling He, who served as co-first author of the study with Natalia de Val, a researcher at TSRI at the time of the study.

    It was a feat of geometry and engineering—and it worked. “It has been really challenging to properly present HIV Env on nanoparticles while keeping its natural trimeric form—but we did it,” said Zhu, “Multiple copies of Env are now displayed on the nanoparticle surface, just like what a real virus would do.”

    The team then tested different nanoparticles and versions of the trimer, including one based on the stabilized Env in the first study, to find the best combinations. Six designs worked well in laboratory tests and now await trials in animal models.

    “We are still pushing hard to find new vaccine candidates to elicit a protective response in humans,” said Wilson. “The challenges going forward are to understand how to use these new vaccine candidates to induce a protective broadly neutralizing antibody response and to develop the appropriate regimens to initiative this response.”

    In addition to Zhu, Wilson, Ward, Kong, He and de Val, authors of the first study, “Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability,” were Nemil Vora, Charles D. Morris, Parisa Azadnia and Bin Zhou of TSRI; Devin Sok of TSRI, the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and Collaboration for AIDS Vaccine Discovery (CAVD), and TSRI Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID); and Dennis R. Burton of TSRI, IAVI, CHAVI-ID and the Ragon Institute.

    This study was supported by the NIH National Institute of General Medical Sciences (NIGMS) (grants P41GM103393, U54 GM094586 and AI084817), the NIH National Center for Research Resources (grant P41RR001209), the IAVI Neutralizing Antibody Center and CAVD (grants OPP1084519 and OPP1115782), CHAVI-ID (grant CHAVI-ID UM1 AI100663), the HIV Vaccine Research and Design (HIVRAD) program (grant P01 AI110657), and American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research. Use of the Advanced Photon Source (APS) beamline 23ID-B and Stanford Synchrotron Radiation Lightsource (SSRL) BL12-2 for this study was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357 and the DOE Office of Biological and Environmental Research.

    In addition to the authors listed above, authors of the second study, “Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles,” were Therese C. Thinnes and David Nemazee of TSRI.

    This study was supported by the IAVI Neutralizing Antibody Center and CAVD, CHAVI-ID (grant UM1 AI00663), the HIV Vaccine Research and Design (HIVRAD) program (grant P01 AI110657) and the Joint Center of Structural Genomics, funded by the NIGMS Protein Structure Initiative (grants U54 GM094586, AI073148 and AI084817).

    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
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    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 2:36 pm on June 17, 2016 Permalink | Reply
    Tags: , New TSRI Method Opens Door to Development of Many New Medicines, Scripps Institute   

    From Scripps: “New TSRI Method Opens Door to Development of Many New Medicines” 

    Scripps
    Scripps Research Institute

    June 20, 2016

    Scientists at The Scripps Research Institute (TSRI) have developed a powerful new method for finding drug candidates that bind to specific proteins.

    The new method, reported recently in Nature, is a significant advance because it can be applied to a large set of proteins at once, even to the thousands of distinct proteins directly in their native cellular environment. The TSRI researchers demonstrated the technique to find “ligands” (binding partners) for many proteins previously thought to bind poorly to small molecules that can be used to determine the functions of their protein targets and can serve as starting compounds for the development of drugs.

    Among the newly discovered ligands are selective inhibitors of two caspase enzymes, which have key roles in multiple diseases but have largely eluded efforts to target them with drugs.

    “Our data suggest that the human proteome is much more broadly targetable with small molecules than has been previously appreciated,” said principal investigator Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Dorris Neuroscience Center and Skaggs Institute for Chemical Biology at TSRI. “That opens up new possibilities for developing scientific probes and ultimately drugs.”

    Putting Fragments to Use

    Researchers have long sought better ways to identify small-molecule ligands for human proteins and to determine which proteins in our cells are inherently “ligandable.” Biologists typically have used complex computer algorithms to predict whether a given class of proteins can bind adequately to small molecules. Pharmaceutical researchers often won’t even try to develop drugs to target proteins that are thought unligandable. Several large protein classes are believed to be in this category, and so far only about 600 of the roughly 20,000 human proteins have been targeted successfully with FDA-approved drugs.

    “There really hasn’t been a way to determine empirically, rather than theoretically, what fraction of the human proteome can be targeted by small molecules,” Cravatt said.

    The new method is partly based on an approach known as fragment-based ligand discovery, which uses candidate ligand molecules about half the size of the small molecules in pill-based drugs. For initial screens to find potential ligands, such “fragment” molecules are much more efficient than drug-sized molecules, requiring much smaller libraries of compounds for a thorough search.

    Cravatt’s team attached candidate fragment molecules to a class of other molecules that, when they can get close enough, react strongly with cysteine amino-acids on proteins, locking the ligands to the proteins with strong “covalent” bonds.

    “You still need an affinity-based interaction, but the covalent bonding event provides a significant boost in potency,” said Keriann M. Backus, a research associate in the Cravatt laboratory who is first author of the study with TSRI Professional Scientific Collaborator Bruno Correia.

    The scientists devised a screening system in which they can apply these covalent-bonding fragment molecules one by one to entire collections of proteins expressed in human cells. The method can even be used with intact, living cells in a culture dish. The system allows researchers to detect and identify which small-molecule fragments have bound covalently to which proteins in the samples and which specific sites on the proteins are responsible for binding.

    Applying a small library of cysteine-reactive fragments to the proteins found in two types of human cancer cells, the scientists found that the fragments successfully “liganded” more than 750 different cysteines found on more than 600 distinct proteins—which equated to more than 20 percent of all the proteins assayed in the samples.

    Many of these proteins belonged to protein classes, such as transcription factors, that have been considered virtually unligandable, and therefore “undruggable.” In fact, about 85 percent of the newly liganded proteins are not listed in a standard database of proteins with known small-molecule ligands.

    “This experiment has effectively expanded what we think of as the ligandable proteome,” said Backus.

    Potential to Develop Probes and Drugs

    The researchers were able to confirm the accuracy of the system, for example, by showing that it can identify the known protein targets of a covalent-binding anti-cancer drug, ibrutinib.

    The team also demonstrated that some of the protein-binding ligand molecules identified with the system have strong biological activity—and thus have the potential to be developed into scientific probes or drugs. Newly discovered ligands for the enzymes IDH1 and IDH2, for example, turned out to block the activity of the normal versions of the enzymes as well as the mutant versions implicated in many cancers.

    In a final set of experiments, the team showed that one of its identified ligands inhibits the activities of caspase-8 and caspase-10, two enzymes that help switch on the cellular self-destruct process known as apoptosis. An excess of apoptosis is thought to contribute to neurodegenerative conditions such as Alzheimer’s and Huntington’s disease, as well as the brain damage occurring in the aftermath of strokes and other brain injuries. By contrast, a lack of apoptosis in certain cells is believed to contribute to cancers and autoimmune diseases. However, scientists don’t understand enough about the roles of these enzymes, since they have been largely unable to find small molecules that selectively inhibit specific caspases.

    In this case, Cravatt’s team found that their initially identified anti-caspase ligand works by binding the precursor forms of caspase-8 and -10. They chemically modified the ligand into one that selectively binds just the precursor of caspase-8, and, using their two ligands as probes, were able to discover new details of how caspase-8 and -10 promote apoptosis in human T-cells.

    “In essence, we demonstrated that our new platform works and that we can use the ligands it identifies to do useful biology,” said Backus.

    Backus and other members of the Cravatt laboratory are now doing several further studies: optimizing many of the newly identified ligands into probes for exploring protein functions; making a more comprehensive catalogue of cysteine-containing proteins that are ligandable; and expanding the method to target other amino-acids besides cysteine.

    “We will be occupied for some time following up on this development,” said Cravatt.

    Other co-authors of the paper, Proteome-wide covalent ligand discovery in native biological systems, were Kenneth M. Lum, Stefano Forli, Benjamin D. Horning, Gonzalo E. González-Páez, Sandip Chatterjee, Bryan R. Lanning, John R. Teijaro, Arthur J. Olson, and Dennis W. Wolan, all of TSRI.

    Funding was provided by the National Institutes of Health (CA087660, GM090294, GM108208, GM069832).

    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 2:25 pm on June 3, 2016 Permalink | Reply
    Tags: , , Celebrex fights cancer, Scripps Institute   

    From Scripps: “Scientists Show Commonly Prescribed Painkiller Slows Cancer Growth” 

    Scripps
    Scripps Research Institute

    June 06, 2016
    By Eric Sauter

    Scientists from the Florida campus of The Scripps Research Institute (TSRI) have found that one of the most widely prescribed pain and anti-inflammation drugs slows the growth rate of a specific kind of cancer in animal models and suggests the medication could have the same effect on other types of tumors.

    The new study, published online ahead of print by the journal Cancer Research, focused on the effects of celecoxib (Pfizer’s Celebrex®).

    Celebrex® targets an enzyme called “cyclooxygenase-2” (COX-2), which is linked to pain and inflammation. This enzyme is also critical in the creation of prostaglandins, compounds that act like hormones and play a role in promoting tumor growth. COX-2 expression is typically low in normal tissue, but high in multiple types of cancers.

    “We were actually interested in determining what a particular signaling pathway does in cancer,” said TSRI Associate Professor Joseph Kissil, who led the study. “In the process, we found that it activates genes that promote survival of tumor cells and that they do so by turning on enzymes involved in inflammation, including COX2, which anti-inflammatory drugs like Celebrex® inhibit.”

    1
    Authors of the new study included (left to right) Smitha Kota, William Guerrant, Joseph Kissil, Scott Troutman and Vinay Mandati.

    The researchers went on to conduct animal studies tracking the effects of celecoxib on the growth of cancer cells from a tumor type known as neurofibromatosis type II (NF2). In humans, NF2 is a relatively rare inherited form of cancer caused by mutations in the anti-tumor gene NF2, which leads to benign tumors of the auditory nerve.

    Animals received a daily dose of the drug, and tumor growth was followed by imaging. Analysis of the results showed a significantly slower tumor growth rate in celecoxib-treated models than in controls.

    Using various approaches, the new study also showed that a signaling cascade known as the Hippo-YAP pathway is involved in these results and that the protein YAP is required for the proliferation and survival of NF2 cells and tumor formation.

    “Our study shows that COX2 inhibitors do have an effect on the tumor cells,” said TSRI Research Associate William Guerrant, the study’s first author. “They also have an impact on inflammatory responses that play a role in tumor growth. It’s possible that in other cancers these effects might actually be stronger because of the drug’s impact on inflammation.”

    In addition to Kissil and Guerrant, other authors of the study, “YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2–EGFR Signaling Axis,” are Smitha Kota, Scott Troutman, Vinay Mandati and Mohammad Fallahi of TSRI; and Anat Stemmer-Rachamimov of Massachusetts General Hospital.

    The work was supported by the National Institutes of Health (grants NS077952 and CA124495). Guerrant is also a recipient of a Young Investigator Award from the Children’s Tumor Foundation.

    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 2:05 pm on June 3, 2016 Permalink | Reply
    Tags: , , Scripps Institute, Venom based therapies   

    From Scripps: “Harnessing Nature’s Vast Array of Venoms for Drug Discovery” 

    Scripps
    Scripps Research Institute

    June 06, 2016
    No writer credit found

    There are lessons to be learned from venoms.

    Scorpions, snakes, snails, frogs and other creatures are thought to produce tens or even hundreds of millions of distinct venoms. These venoms have been honed to strike specific targets in the body.

    For victims of a scorpion’s sting, that spells doom. For scientists, however, the potent molecules in venoms hold the potential to be adapted into medicines. But venoms are difficult to isolate and analyze using traditional methods, so only a handful have been turned into drugs.

    Now a team led by scientists at The Scripps Research Institute (TSRI) has invented a method for rapidly identifying venoms that strike a specific target in the body—and optimizing such venoms for therapeutic use.

    The researchers demonstrated the new method by using it to identify venoms that block a certain protein on T cells—a protein implicated in multiple sclerosis, rheumatoid arthritis and other inflammatory disorders. The researchers then used their method to find an optimized, long-acting variant of a venom that blocks this protein and showed that the new molecule powerfully reduces inflammation in mice.

    “Until now we haven’t had a way to seriously harness venoms’ vast therapeutic potential,” said principal investigator Richard A. Lerner, Lita Annenberg Hazen Professor of Immunochemistry at TSRI.

    The report on the advance by Lerner and his colleagues was selected as a “Hot Paper”* and cover story by the journal Angewandte Chemie.

    Choose Your Poison

    The use of venoms as therapies may seem paradoxical, since these molecules generally evolved to harm and kill other organisms. But a low dose delivered to the right place can sometimes have highly beneficial effects. The pain-killing drug ziconotide (Prialt®), for example, is derived from one of the venoms used by cone-snails to immobilize their fishy prey. Venoms also are attractive from a drug development perspective because they tend to hit their targets on cells with very high potency and selectivity.

    Drug companies would have adapted far more venoms into therapies by now, but the traditional method of determining the biological target of a venom is slow, difficult and expensive. It involves the extraction of relatively large quantities of venom from the animal species in question, followed by purification of the molecules and laborious lab-dish tests to see how they affect cells.

    The new method is geared for speed and involves the extraction only of information—with little direct involvement of venomous creatures. To start, the TSRI-led team, including first author Hongkai Zhang, a senior scientist in the Lerner laboratory, consulted animal toxin databases and assembled a list of 589 venoms whose protein sequences have features of interest. They then synthesized the venoms’ genes and inserted them into special viruses that deliver genes into cells.

    The aim in this initial, proof-of-principle project was to find venoms that block a potassium ion-channel protein known as Kv1.3. Ion channels allow charged molecules to flow in and out of cells, and are involved in a variety of essential biological functions—which makes them common targets of venoms. Kv1.3 is of special interest to the pharmaceutical industry because it appears to facilitate the proliferation and migration of T-cells that drive inflammatory disorders such as multiple sclerosis. Drugs that block Kv1.3 are already under development.

    To screen their library of venoms for those that block Kv1.3, the researchers, including a team of collaborating biologists at the Institute for Advanced Immunochemical Studies at ShanghaiTech University, used a cell-based selection system of a type developed by Lerner, Zhang and colleagues in 2012. They created a culture of special Kv1.3-containing test cells in which a strong interaction between a venom and a Kv1.3 ion channel would switch on a red fluorescence gene. The researchers distributed the venom-gene-carrying viruses among the cells and used a fast, automated system to select the cells that showed strong fluorescence. Standard molecular biology techniques were then used to identify and quantify the venom genes these cells contained. The researchers repeated this selection process for three rounds to see which venom genes became most abundant in the cells.

    In this way, the team soon identified 27 likely Kv1.3-blocking venoms. All but two turned out to be known blockers of the ion channel. Another had been reported in the literature as a suspected potassium-channel blocker, and the last, an uncharacterized scorpion venom called CllTx1, proved in subsequent traditional-method testing—using actual venom extracted from a scorpion—to be a potent Kv1.3 blocker.

    Optimal Pharmaceutical Properties

    The team realized that their selection system could be useful not only for screening libraries of natural venoms but also for screening artificial variants or “analogs” of a given venom to find those with optimal pharmaceutical properties. To demonstrate, they generated about a million analogs of a long-acting protein based on ShK, a sea anemone toxin that blocks Kv1.3, and put the analogs through three rounds of selection to find the best one. The resulting candidate, S1-2, showed a strong effect not only for blocking Kv1.3 but also for reducing inflammation in a standard rodent model.

    “This analog appears to be very potent against Kv1.3 and has no off-target effects on closely related ion channels,” said Zhang.

    Zhang, Lerner and their colleagues now plan to use their method with much larger venom datasets to find more drug candidates. “We’re particularly interested in finding venoms that block sodium ion channels involved in pain,” Lerner said.

    In addition to Lerner and Zhang, co-authors of the paper, Autocrine-Based Selection of Drugs that Target Ion Channels from Combinatorial Venom Peptide Libraries, were Mingjuan Du, Xiao Liu, Jingying Sun, Wei Wang and Xiu Xin of ShanghaiTech University; Lourival D. Possani of the National Autonomous University of Mexico, who purified the scorpion toxin CllTx1 for analysis; and Jia Xie and Kyungmoo Yea of TSRI.

    Funding for the research was provided by the JPB foundation, Zebra Biologics and ShanghaiTech 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 3:02 pm on May 26, 2016 Permalink | Reply
    Tags: , , Scripps Institute, TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers   

    From Scripps: “TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers” 

    Scripps
    Scripps Research Institute

    Scientists at The Scripps Research Institute (TSRI) have caught a cancer-causing mutation in the act.

    A new study shows how a gene mutation found in several human cancers, including leukemia, gliomas and melanoma, promotes the growth of aggressive tumors.

    “We’ve found the mechanism through which this mutation leads to a scrambling of the genome,” said TSRI Associate Professor Eros Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York University (NYU) School of Medicine. “That’s when you get really massive tumors.”

    The research, published* May 26, 2016 by the journal Cell Reports, also suggests a possible way to kill these kinds of tumors by targeting an important enzyme.

    A Puzzling Finding

    The researchers investigated mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.

    POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme, called ATR, that triggers programmed cell death.

    Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukemia and melanoma.

    “Somehow those cells found a way to survive—and thrive,” said Lazzerini Denchi. “We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

    It Takes Two to Tango

    Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.

    “The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” said Lazzerini Denchi.

    P53, a well-known tumor suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumors.

    The findings led the team to consider a new strategy for killing these tumors.

    Scientists know that all cells—even cancer cells—will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumors without affecting healthy cells. “This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” said Lazzerini Denchi.

    The researchers plan to investigate this new therapeutic approach in future studies.

    In addition to Lazzerini Denchi and Sfeir, authors of the study, “Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis,” were Angela Beal and Nidhi Nair of TSRI; Alexandra M. Pinzaru, Aaron F. Phillips, Eric Ni and Timothy Cardozo of the NYU School of Medicine; Robert A. Hom and Deborah S. Wuttke of the University of Colorado; and Jaehyuk Choi of Northwestern University.

    The study was supported by the National Institutes of Health (grants AG038677, CA195767 and GM059414), a NYSTEM institutional training grant (C026880), a scholarship from the California Institute for Regenerative Medicine, a Ruth L. Kirschstein National Research Service Award (GM100532), The V Foundation for Cancer Research, two Pew Stewart Scholars Awards and the Novartis Advanced Discovery Institute.

    *Science paper:
    Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

    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 8:47 pm on May 20, 2016 Permalink | Reply
    Tags: , , Scripps Institute   

    From Scripps: “Researchers Pioneer a Breakthrough Approach to Breast Cancer Treatment” 

    Scripps
    Scripps Research Institute

    May 23, 2016
    Eric Sauter

    In a development that could lead to a new generation of drugs to precisely treat a range of diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have for the first time designed a drug candidate that decreases the growth of tumor cells in animal models in one of the hardest to treat cancers—triple negative breast cancer.

    “This is the first example of taking a genetic sequence and designing a drug candidate that works effectively in an animal model against triple negative breast cancer,” said TSRI Professor Matthew Disney.

    1
    “The study represents a clear breakthrough in precision medicine, as this molecule only kills the cancer cells that express the cancer-causing gene—not healthy cells,” says Professor Matthew Disney. (Photo by James McEntee.)

    The study*, published online ahead of print the week of May 9, 2016, by the journal Proceedings of the National Academy of Sciences, demonstrates that the Disney lab’s compound, known as Targaprimir-96, triggers breast cancer cells to kill themselves via programmed cell death by precisely targeting a specific RNA that ignites the cancer.

    Short-Cut to Drug Candidates

    While the goal of precision medicine is to identify drugs that selectively affect disease-causing biomolecules, the process has typically involved time-consuming and expensive high-throughput screens to test millions of potential drug candidates to identify those few that affect the target of interest. Disney’s approach eliminates these screens.

    The new study uses the lab’s computational approach called Inforna, which focuses on developing designer compounds that bind to RNA folds, particularly microRNAs.

    MicroRNAs are short molecules that work within all animal and plant cells, typically functioning as a “dimmer switch” for one or more genes, binding to the transcripts of those genes and preventing protein production. Some microRNAs have been associated with diseases. For example, microRNA-96, which was the target of the new study, promotes cancer by discouraging programmed cell death, which can rid the body of cells that grow out of control.

    In the new study, the drug candidate was tested in animal models over a 21-day course of treatment. Results showed decreased production of microRNA-96 and increased programmed cell death, significantly reducing tumor growth. Since targaprimir-96 was highly selective in its targeting, healthy cells were unaffected.

    In contrast, Disney noted, a typical cancer therapeutic targets and kills cells indiscriminately, often leading to side effects that can make these drugs difficult for patients to tolerate.

    “In the future we hope to apply this strategy to target other disease-causing RNAs, which range from incurable cancers to important viral pathogens such as Zika and Ebola,” added Research Associate Sai Pradeep Velagapudi, the first author of the study and a member of the Disney lab.

    [Alex Perryman, formerly at Scripps, a veteran of the Scripps project FightAids@home on World Community Grid and now at Rutgers University is leading the new WCG project OpenZika. WCG also has OutsmartEbolaTogether at Scripps]

    WCGLarge

    Rutgers Open Zika

    Outsmart Ebola Together

    2
    “In the future we hope to apply this strategy to target other disease-causing RNAs, which range from incurable cancers to important viral pathogens such as Zika and Ebola,” says Research Associate Sai Pradeep Velagapudi.

    In addition to Disney and Velagapudi, authors of the study, “Design of a Small Molecule Against an Oncogenic Non-coding RNA,” were Michael D. Cameron, Christopher L. Haga, Laura H. Rosenberg, Marie Lafitte, Derek Duckett and Donald G. Phinney of TSRI.

    The work was supported by the National Institutes of Health (R01GM9455) and The Nelson Fund for Therapeutic Development.

    *Science paper:
    Design of a small molecule against an oncogenic noncoding RNA

    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 10:46 am on May 10, 2016 Permalink | Reply
    Tags: , , Scripps Florida Scientists Design Potent Therapeutic 'Warheads' That Target Cancer Cells, Scripps Institute   

    From Scripps: “Scripps Florida Scientists Design Potent Therapeutic ‘Warheads’ That Target Cancer Cells” 

    Scripps
    Scripps Research Institute

    May 9, 2016

    In a pair of related studies, chemists from the Florida campus of The Scripps Research Institute (TSRI) have identified and designed dozens of molecular “warheads” that not only can detect a key biomarker of cancer, but also could be developed into a potent new class of drug candidates for a range of diseases.

    A number of these molecules are already “hidden” in drugs approved by the U.S. Food and Drug Administration (FDA), raising the possibility that these widely used pharmaceuticals could be made even more effective using more potent/selective covalent inhibitors or “warheads.”

    The studies, which were published recently in the journals Chemical Science and Chemical Communication, were led by TSRI Associate Professor Kate Carroll.

    The molecules in question are known as “nucleophiles” (literally, nucleus lovers), which share their electrons with “electrophiles” (literally, electron lovers) and serve as their atomic dance partners. This sharing of electrons creates an interaction known as a covalent bond, which some consider the fundamental basis of chemical reactivity.

    Electrophiles have been available to the scientific community for decades for use as tools to probe levels of cysteine sulfenic acid—a marker for cancer and other diseases—and to install as “warheads” or covalent modifiers in drugs that target high levels of sulfenic acid in cells.

    The downside of electrophiles is that they compete with high concentrations of off-target nucleophiles in the cell, such as glutathione. In addition, this class of covalent inhibitors indiscriminately targets the protein in healthy and diseased cells. “To counteract this effect, our complementary approach would use nucleophile ‘warheads’ attached to a binding scaffold that would target sulfenic acid on therapeutically important proteins in unhealthy cells under oxidative stress,” said Carroll.

    To produce a library of “designer” nucleophiles with far greater reactivity, Carroll and her colleague, Senior Research Associate Vinayak Gupta, developed a unique screen. So far, some of the nucleophiles they identified possess more than 200 times the current standard for sulfenic acid probes.

    “We now have about 150 of these ‘warheads’ in our library,” Carroll said.

    While the greater interest in the scientific community has been in electrophiles, the TSRI team also examined previously unidentified nucleophilic functional groups, such as those within the Pfizer rheumatoid arthritis drug tofacitinib (XELJANZ®).

    “The nucleophiles we identified in this study represent the first covalent strategy to target sulfenic acid that should be highly enabling for the drug discovery community,” Gupta said. “Moreover, our findings that tofacitinib reacts robustly with sulfenic acid shows that ‘warheads’ or other functional groups in these drugs may indeed have new or alternative mechanisms of action.”

    Carroll added, “Tofacitinib may have multiple modes of action that include a nucleophile targeting cysteine sulfenic acid in the active site of JAK kinases. If the nucleophile contributes positively to therapeutic outcome, it might be possible to optimize that chemical property and make the drug more effective.”

    Carroll says she uncovers more instances of nucleophiles “hidden in plain sight” every day, suggesting that nucleophiles may, in fact, be unsung central players in these reactions.

    The studies, Profiling the Reactivity of Cyclic C-Nucleophiles towards Electrophilic Sulfur in Cysteine Sulfenic Acid, and Rational Design of Reversible and Irreversible Cysteine Sulfenic Acid-Targeted Linear C-Nucleophiles, were published in Chemical Science and Chemical Communications, respectively.

    The work was supported by the National Institutes of Health (grant numbers R01 GM102187 and R01 CA174864).

    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 1:51 pm on April 27, 2016 Permalink | Reply
    Tags: , MicroRNA’s Role in Memory, Scripps Institute, Sleep and Synapse Function   

    From Scripps: “TSRI, Harvard, Stanford and Brandeis Collaborate to Study MicroRNA’s Role in Memory, Sleep and Synapse Function” 

    Scripps
    Scripps Research Institute

    April 27, 2016

    A group including scientists from the Florida campus of The Scripps Research Institute (TSRI) has been awarded a grant from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health to study the role of microRNAs in a range of physiological activities, including memory, sleep, synapse function and movement.

    Ron Davis, chair of TSRI’s Department of Neuroscience, will be a principal investigator of the new five-year study with David Van Vactor of Harvard University, Leslie Griffith of Brandeis University and Dennis Wall of Stanford University.

    “This new collaboration with some of the best scientists at some of the best universities in the world has the potential to bring us a wealth of new and potentially groundbreaking knowledge about microRNAs,” Davis said. “Because microRNAs are so critical for normal development and physiology, they are a potentially rich source of therapeutic targets. Our new collaboration will help us exploit that potential.”

    Scripps Florida will receive approximately $2 million for the project over the next five years.

    MicroRNAs, as their name suggests, are tiny bits of genetic material. Instead of being translated into proteins like many RNAs, microRNAs act to regulate gene expression—acting like a dimmer switch on a light.

    In humans there are almost 2,000 distinct microRNAs, which collectively regulate somewhere between 30 and 80 percent of human genes.

    Despite their ubiquity, their importance has become evident only in the last decade or so, and details are still emerging. Davis noted a host of critical questions remain: How complex is the microRNA regulatory landscape for neural circuits mediating essential behaviors? To what extent are microRNA mechanisms used in the brain? Do they regulate distinct sets of target genes in different cell types and/or developmental stages?

    The new collaborative study will use Drosophila, the common fruit fly, which is a widely recognized substitute for human memory studies, to help answer some of these questions.

    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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