Tagged: HMS- Harvard Medical School Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 10:15 am on March 20, 2017 Permalink | Reply
    Tags: Angelman’s syndrome, , , Cerebellin 1 (CBLN1), Chemogenetics, Circuit Breaker, HMS- Harvard Medical School, Isodicentric chromosome 15q, , The gene UBE3A   

    From HMS: “Circuit Breaker” Autism Studies 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    March 16, 2017
    JACQUELINE MITCHELL

    1
    ktsimage/Getty Images

    Harvard Medical School researchers at Beth Israel Deaconess Medical Center have gained new insight into the genetic and neuronal circuit mechanisms that may contribute to impaired sociability in some forms of autism spectrum disorder.

    Led by Matthew Anderson, HMS associate professor of pathology and director of neuropathology at Beth Israel Deaconess, the scientists determined how a gene linked to one common form of autism works in a specific population of brain cells to impair sociability.

    The research, published today in the journal Nature, reveals the neurobiological control of sociability and could represent important first steps toward interventions for patients with autism.

    Anderson and colleagues focused on the gene UBE3A, multiple copies of which cause a form of autism in humans (called isodicentric chromosome 15q). Conversely, the lack of this same gene in humans leads to a developmental disorder called Angelman’s syndrome, characterized by increased sociability.

    In previous work, Anderson’s team demonstrated that mice engineered with extra copies of the UBE3A gene show impaired sociability, as well as heightened repetitive self grooming and reduced vocalizations with other mice.

    “In this study, we wanted to determine where in the brain this social behavior deficit arises and where and how increases of the UBE3A gene repress it,” said Anderson, who is also director of the Autism BrainNET, Boston Node.

    “We had tools in hand that we built ourselves. We not only introduced the gene into specific brain regions of the mouse, but we could also direct it to specific cell types to test which ones played a role in regulating sociability,” Anderson said.

    When Anderson and colleagues compared the brains of the mice engineered to model autism to those of normal—or wild type—mice, they observed that the increased UBE3A gene copies interacted with nearly 600 other genes.

    After analyzing and comparing protein interactions between the UBE3A regulated gene and genes altered in human autism, the researchers noticed that increased doses of UBE3A repressed Cerebellin genes.

    Cerebellin is a family of genes that physically interact with other autism genes to form glutamatergic synapses, the junctions where neurons communicate with each other via the neurotransmitter glutamate.

    The researchers chose to focus on one of them, Cerebellin 1 (CBLN1), as the potential mediator of UBE3A’s effects. When they deleted CBLN1 in glutamate neurons, they recreated the same impaired sociability produced by increased UBE3A.

    “Selecting Cerebellin 1 out of hundreds of other potential targets was something of a leap of faith,” Anderson said. “When we deleted the gene and were able to reconstitute the social deficits, that was the moment we realized we’d hit the right target. Cerebellin 1 was the gene repressed by UBE3A that seemed to mediate its effects,” he said.

    In another series of experiments, Anderson and colleagues demonstrated an even more definitive link between UBE3A and CBLN1. Seizures are a common symptom among people with autism including this genetic form.

    Seizures themselves, when sufficiently severe, also impaired sociability.

    Anderson’s team suspected this seizure-induced impairment of sociability was the result of repressing the Cerebellin genes. Indeed, the researchers found that deleting UBE3A, upstream from Cerebellin genes, prevented the seizure-induced social impairments and blocked seizures ability to repress CBLN1.

    “If you take away UBE3A, seizures can’t repress sociability or Cerebellin,” said Anderson. “The flip side is, if you have just a little extra UBE3A—as a subset of people with autism do—and you combine that with less severe seizures, you can get a full-blown loss of social interactions.”

    The researchers next conducted a variety of brain-mapping experiments to locate where in the brain these crucial seizure-gene interactions take place.

    “We mapped this seat of sociability to a surprising location,“ Anderson explained. Most scientists would have thought they take place in the cortex—the area of the brain where sensory processing and motor commands take place—but, in fact, these interactions take place in the brain stem, in the reward system.”

    Then the researchers used their engineered mouse model to confirm the precise location as the ventral tegmental area, part of the midbrain that plays a role in the reward system and addiction.

    Anderson and colleagues used chemogenetics—an approach that makes use of modified receptors introduced into neurons that respond to drugs but not to naturally occurring neurotransmitters—to switch this specific group of neurons on or off.

    Turning these neurons on could magnify sociability and rescue seizure and UBE3A-induced sociability deficits.

    “We were able to abolish sociability by inhibiting these neurons, and we could magnify and prolong sociability by turning them on,” said Anderson. “So we have a toggle switch for sociability. It has a therapeutic flavor; someday, we might be able to translate this into a treatment that will helps patients.”

    The researchers thank Oriana DiStefano, Greg Salimando and Rebecca Broadhurst for colony work and the HMS Neurobiology Imaging Facility (NINDS P30 Core Center Grant #NS07203).

    This work was supported an American Academy of Neurology Research Training Fellowship, the National Institutes of Health (grants 1R25NS070682, 1R01NS08916, 1R21MH100868 and 1R21HD079249), the Nancy Lurie Marks Family Foundation, the Landreth Family Foundation, the Simons Foundation, Autism Speaks/National Alliance for Autism Research and the Klarman Family Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 10:19 am on February 14, 2017 Permalink | Reply
    Tags: , HMS- Harvard Medical School, , Stem Cells Step Forward   

    From HMS: “Stem Cells Step Forward” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    February 8, 2017
    NANCY FLIESLER

    For first time, iPS cells flag potential drug for blood disease.

    1
    Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s.

    Researchers at Harvard Medical School and Boston Children’s Hospital were able, for the first time, to use patients’ own cells to create cells similar to those in bone marrow and then use them to identify potential treatments for a blood disorder.

    The work was published Feb. 8 in Science Translational Medicine.

    The team derived the so-called blood progenitor cells from two patients with Diamond-Blackfan anemia (DBA), a rare, severe blood disorder in which the bone marrow cannot make enough oxygen-carrying red blood cells.

    The researchers first converted some of the patients’ skin cells into induced pluripotent stem (iPS) cells. They then got the iPS cells to make blood progenitor cells, which they loaded into a high-throughput drug-screening system.

    Testing a library of 1,440 chemicals, the team found several that showed promise in a dish. One compound, SMER28, was able to get live mice and zebrafish to start churning out red blood cells.

    The study marks an important advance in the stem cell field. iPS cells, theoretically capable of making virtually any cell type, were first created in the lab in 2006 from skin cells treated with genetic reprogramming factors. Specialized cells generated by iPS cells have been used to look for drugs for a variety of diseases—except for blood disorders, because of technical problems in getting iPS cells to make blood cells.

    “iPS cells have been hard to instruct when it comes to making blood,” said Sergei Doulatov, former HMS research fellow at Boston Children’s and co-first author on the paper with doctoral student Linda Vo and research fellow Elizabeth Macari. “This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

    DBA is currently treated with steroids, but these drugs help only about half of patients, and some of them eventually stop responding. When steroids fail, patients must receive lifelong blood transfusions, and quality of life for many patients is poor. The researchers believe SMER28 or a similar compound might offer another option.

    “It is very satisfying as physician-scientists to find new potential treatments for rare blood diseases such as Diamond-Blackfan anemia,” said Leonard Zon, HMS Grousbeck Professor of Pediatrics and director of the Stem Cell Research Program at Boston Children’s and co-corresponding author on the paper.

    “This work illustrates a wonderful triumph,” said co-corresponding author George Q. Daley, dean of HMS and associate director of the Stem Cell Research Program.

    Making red blood cells

    As in DBA itself, the patient-derived blood progenitor cells, studied in a dish, failed to generate the precursors of red blood cells, known as erythroid cells. The same was true when the cells were transplanted into mice. But the chemical screen got several “hits”: in wells loaded with these chemicals, erythroid cells began appearing.

    Because of its especially strong effect, SMER28 was put through additional testing. When used to treat the marrow in zebrafish and mouse models of DBA, the animals made erythroid progenitor cells that in turn made red blood cells, reversing or stabilizing anemia.

    The same was true in cells from DBA patients transplanted into mice. The higher the dose of SMER28, the more red blood cells were produced, and no ill effects were found. Formal toxicity studies have not yet been conducted.

    Circumventing a roadblock

    Previous researchers have tried for years to isolate blood stem cells from patients. They have sometimes succeeded, but the cells are very rare and cannot create enough copies of themselves to be useful for research. Attempts to get iPS cells to make blood stem cells have also failed.

    The HMS and Boston Children’s researchers were able to circumvent these problems by instead transforming iPS cells into blood progenitor cells using a combination of five reprogramming factors. Blood progenitor cells share many properties with blood stem cells and are readily multiplied in a dish.

    “Drug screens are usually done in duplicate, in tens of thousands of wells, so you need a lot of cells,” said Doulatov, who now heads a lab at the University of Washington. “Although blood progenitor cells aren’t bona fide stem cells, they are multipotent and they made red cells just fine.”

    SMER28 has been tested preclinically for some neurodegenerative diseases. It activates a so-called autophagy pathway that recycles damaged cellular components. In DBA, SMER28 appears to turn on autophagy in erythroid progenitors. Doulatov plans to further explore how this interferes with red blood cell production.

    Zon and Daley have been awarded NIH funding from the National Heart, Lung and Blood Institute’s Progenitor Cell Translational Consortium to further explore several promising compounds identified through the study.

    The study was supported by grants from the National Institutes of Health (R24-DK092760, R24-DK49216, UO1-HL100001, R01HL04880, AQ42R24OD017870-01), Alex’s Lemonade Stand, the Taub Foundation Grants Program for MDS AQ43 Research and the Doris Duke Medical Foundation. Additional funding came from a National Science Foundation Graduate Research Fellowship and NHLBI grant 1F32HL124948-01.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
  • richardmitnick 11:25 am on February 6, 2017 Permalink | Reply
    Tags: , , HMS- Harvard Medical School, , Mullerian Inhibiting Substance (MIS), Ovarian Chemo Shield?   

    From HMS: “Ovarian Chemo Shield?” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    January 30, 2017
    SUE MCGREEVEY

    A hormone that plays a role in fetal development may help protect the ovaries from chemo damage.

    1
    Scientists report that a naturally occurring hormone that plays a role in fetal development may help protect the ovaries from chemo damage. Photo credit: Magicmine/Getty Images.

    A naturally occurring hormone that plays an important role in fetal development may be the basis for a new type of reversible contraceptive that can protect ovaries from the damage caused by chemotherapy drugs.

    In their report receiving online publication in PNAS, a team from the Pediatric Surgical Research Laboratories in the Harvard-affiliated Massachusetts General Hospital (MGH) Department of Surgery describes using Mullerian Inhibiting Substance (MIS) to halt, in a mouse model, the early development of the ovarian follicles in which oocytes mature, an accomplishment that protects these primordial follicles from chemotherapy-induced damage.

    “MIS has long been suspected as an inhibitor of the initial stages of follicular development, but the complete blockade of the process was unexpected and opened up a number of new applications for the hormone,” said corresponding author David Pepin, an assistant professor of Surgery at Harvard Medical School (HMS).

    “Because most of what we know about female reproduction is focused on the late stages of follicle maturation, our current therapies – including contraceptive drugs – are all targeted at those processes.

    The ability to target earlier stages and potentially maintain the larger pool of quiescent oocytes called the ovarian reserve not only could maintain fertility during chemotherapy but also could be applied to modern fertility treatments,” he said.

    During embryonic development, MIS is secreted by the testes of male embryos to prevent the maturation of structures that would give rise to female reproductive organs.

    Patricia Donahoe, director of the Pediatric Surgical Research Laboratories and a co-author of the PNAS paper, has been investigating the potential use of MIS to treat ovarian cancer and other reproductive tumors for several years.

    As part of that continuing work, Pepin made the surprising observation that overexpression of MIS in female animals completely blocked the maturation of follicles, keeping them at the inactive, primordial stage and rendering the animals infertile.

    Chemotherapy’s anti-cancer effects depend on its ability to damage rapidly growing cells, including cells in maturing ovarian follicles. But chemotherapy is also believed to accelerate the activation of primordial follicles, essentially using up the ovarian reserve over a matter of months instead of years.

    The idea that ovarian suppression could preserve fertility in women undergoing chemotherapy is not new, but the ability to halt activation of primordial follicles during chemotherapy was not previously possible.

    Current hormonal contraceptives act at later stages, after the follicle has been committed to either grow or perish, so the unique action of MIS in maintaining follicles at the primordial stage offered intriguing new possibilities.

    In a series of experiments with female mice, the research team first showed that increasing MIS levels either by twice-daily injection of the purified protein or by gene therapy led to a gradual but significant decrease in the number of growing follicles, leading after several weeks to an almost complete lack of growing follicles but maintaining a consistent level of primordial follicles.

    Halting MIS treatment, either by discontinuing the injections or by transplanting follicle-depleted ovarian tissues from gene-therapy treated mice into untreated control animals, led to resumption of follicle development in as little as 12 days, indicating that the effect is reversible.

    Mice in which MIS levels were elevated by gene therapy gradually lost their fertility, and those with higher MIS levels were completely infertile after six weeks.

    Both methods of MIS administration were able to protect the ovarian reserve from the effects of common chemotherapy drugs, resulting in primordial follicle counts from 1.4 to nearly 3 times higher than in mice not receiving MIS during chemotherapy, with counts depending on the particular chemotherapy drug used and the route of MIS administration.

    “We have just begun to scratch the surface of the implications of MIS for reproductive and overall health,” Pepin said.

    “Its unique mechanism of action means it could be useful in treating many conditions that cause primary ovarian insufficiency or premature menopause. Long-term contraceptive use would probably require replacement of hormones such as estrogen to prevent the side effects of ovarian shutdown, which would be less of a concern for short-term treatment during chemotherapy. Gene therapy with MIS could also offer a nonsurgical alternative to veterinary sterilization procedures,” Pepin said.

    Pepin’s team is now investigating the quality of the oocytes preserved by MIS treatment after chemotherapy, along with elucidating the molecular mechanisms by which MIS inhibits follicle activation, which may lead to the development of small-molecule oral alternatives.

    The researchers have also formed a company, Provulis LLC, to develop clinical applications of MIS treatment and are planning clinical trials.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

     
c
Compose new post
j
Next post/Next comment
k
Previous post/Previous comment
r
Reply
e
Edit
o
Show/Hide comments
t
Go to top
l
Go to login
h
Show/Hide help
shift + esc
Cancel
%d bloggers like this: