Transformative awards for Mocarski's malleable cells, lung fibrosis

The National Institutes of Health has announced a five-year, $1.9 million Transformative Research Award to Emory virologist Edward Mocarski, PhD for his work on how the mechanisms of programmed cell death can be subverted. Mocarski is Robert W. Woodruff professor of microbiology and immunology at Emory University School of Medicine and Emory Vaccine Center. His research, which originated in probing how cells commit suicide when taken over by viruses, could lead to advances in regenerative medicine and organ transplant. The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nine “high-risk-, high-reward” Transformative Research Awards (13 recipients) announced by the NIH on October 6. In the same group this year, Thomas Barker in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University received a Transformative Research Award for his research on mechanosensors + pulmonary fibrosis. The Transformative Research Award program supports “exceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested.” Emory has achieved only one other TRA since the program was established in 2009: Shuming Nie's project on imaging to guide cancer surgery. “This Transformative award was made possible because of the creative and engaged graduate students and postdoctoral fellows I have had working with me at Emory,” Mocarski says. In 2011, Mocarski, working with former graduate student William Kaiser and Emory geneticist Tamara Caspary showed that two complementary forms of programmed cell death, necrosis and apoptosis, can be genetically excised from mice, leaving a viable animal with a functioning immune system. These findings are yielding additional fruit. Mocarski’s research indicates that cells from these genetically altered mice are unexpectedly malleable, in that they are easier to reprogram into induced pluripotent stem cells. Once reprogrammed, induced pluripotent stem cells (iPS cells) can be directed to become cells of almost any tissue, making them promising potential tools for the treatment of many diseases. The genetically altered mice are also less susceptible to deadly inflammation and more readily accept bone marrow transplants. The Transformative project’s aims are to exploit these findings and test the ability of drugs that interfere with programmed cell death to facilitate tissue regeneration, iPS cell reprogramming and transplant.      

Cancer metastasis: isolating invasive cells with a color change

At Winship Cancer Institute, Adam Marcus and Jessica Konen have developed a tool for probing how invasive cells are different, which could lead to new ways to fight cancer metastasis. In the video, check out how they track the behavior of apparently devious "leader cells".

Tools for illuminating brain function make their own light

Hey optogenetics fans, cut (or temporarily put aside) the fiber optic cable. Flexible tools allow the choice between activation by light or an external chemical.

Shannon Gourley

Fragile X syndrome: building a case for a treatment strategy

New research in mice strengthens a potential strategy for treating fragile X syndrome, the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder.

The results, published April 23 in Cell Reports, suggest that a drug strategy targeting a form of the enzyme PI3 (phosphoinositide-3) kinase could improve learning and behavioral flexibility in people with fragile X syndrome. The PI3 kinase strategy represents an alternative to one based on drugs targeting mGluR5 glutamate receptors, which have had difficulty showing benefits in clinical trials.

Research led by Emory scientists Gary Bassell, PhD and Christina Gross, PhD had previously found that the p110β form of PI3 kinase is overactivated in the brain in a mouse fragile X model, and in blood cells from human patients with fragile X syndrome.

Now they have shown that dialing back PI3 kinase overactivation by using genetic tools can alleviate some of the cognitive deficits and behavioral alterations observed in the mouse model. Drugs that target the p110β form of PI3 kinase are already in clinical trials for cancer.

“Further progress in this direction could lead to a clinical trial in fragile X,” says Bassell, who is chair of Cell Biology at Emory University School of Medicine. “The next step is to test whether this type of drug can be effective in the mouse model and in human patient cells.” Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Effects of cocaine exposure in adolescent rodents

Much of neuroscientist Shannon Gourley’s work focuses on the idea that adolescence is a vulnerable time for the developing brain. She and graduate student Lauren DePoy recently published a paper in Frontiers in Pharmacology showing that in adolescent rodents, cocaine exposure can cause the loss of dendritic arbors in part of the brain important for decision-making.

The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for “linking reward to hedonic experience.” It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.

“To make an analogy, it’s like a tree losing some of its leaves,” Gourley writes. “Lauren’s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors – as if entire branches are being cut from the tree.”

The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.

The findings suggest a partial explanation for the increased risk of dependence in people who start using cocaine during adolescence.

Posted on by Quinn Eastman in Neuro Leave a comment

Dissecting how chronic stress leads to depression

How can we study depression and antidepressants in animals? They can’t talk and tell us how they’re feeling. Previously, researchers have used the model of “behavioral despair,” with examples of the forced swimming test or the tail suspension test.

Shannon Gourley, PhD

Several psychiatrists have been arguing that a new framework is needed, which better simulates aspects of depression in humans, such as the variety of behavioral changes and the several week time period needed for antidepressants to function. This new framework could help illuminate how depression develops, and lead to new antidepressants that are effective for more people.

Shannon Gourley, who recently joined the Emory-Children’s Pediatric Research Center has been taking the approach of examining the lack of motivation and self-defeating behavior that are integral parts of depression.

The Pediatric Research Center is an effort led by Emory University and Children’s Healthcare of Atlanta, including partnerships with the Georgia Institute of Technology and Morehouse School of Medicine.

Note: Gretchen Neigh in psychiatry/physiology has been doing work with a similar theme, looking at the effects of adolescent social stress in animal models.

Gourley, neuroscience graduate student Andrew Swanson and their colleagues at Yale, where Gourley was a postdoc with Jane Taylor and Tony Koleske, have a new paper in PNAS on this topic. In particular, they dissect how chronic stress – or exposure to the stress hormone corticosterone – can produce loss of motivation and impaired decision making.

First, the researchers found that exposing rodents to corticosterone shut off a growth factor called BDNF (brain-derived neurotrophic factor) in the frontal cortex, a region of the brain important for planning and goal-directed behavior. BDNF nourishes neurons and helps keep them alive.

To confirm that BDNF was important in this region of the brain, researchers selectively silenced the gene for BDNF only in the frontal cortex. Both mice exposed to stress hormones and the BDNF-altered mice showed reduced motivation to earn food rewards. Mice would ordinarily press a lever dozens of times to get a food pellet, but the BDNF-altered animals would stop trying earlier – the “break point” is 2/3 as high.

“Depression is a leading cause of unemployment because people are unable to break out of self-defeating behavioral patterns and to muster the motivation to engage with the world. If we can better understand how to treat these symptoms, we can effect better outcomes for individuals suffering from depression,” Gourley says. “The BDNF deficiency alone could account for the loss of motivation that individuals with depression suffer.”

However, she reports her team was surprised that the loss of BDNF could not account for another aspect of depression: cyclical self-defeating behavior. They modeled this by asking whether mice continue to press a lever for a food reward even when the reward is no longer available.

“When we made the discovery that reduced BDNF could not account for all of the depression symptoms that we study, we took a step back and looked at the stress response system,” Gourley says.

Stress hormone exposure impairs the ability of mice to switch away from fruitless behaviors, but loss of BDNF in the frontal cortex does not. Here, the stress response system itself was the culprit. When her team temporarily blocked the ability of mice to shut off their stress response systems using the drug mifepristone, mice had impaired decision-making. However, their motivation to obtain rewards was not altered. When the drug wore off, they returned to normal.

Gourley says the implication is that effective antidepressants need to be able to attack not one, but two physiological systems: they need to increase levels of BDNF, and they need to help the stress system recover so that it can shut itself off better. A classic trycyclic antidepressant, amitriptyline, can do both and was effective in treating both the motivation and decision making parts of depression in animal models.

The use of tricyclic antidepressants is limited because of side effects and overdose potential. In addition, another challenge in treating depression is that current antidepressants only begin to work after several weeks or months of treatment. This is thought to be because it takes several weeks for these drugs—which act only indirectly on BDNF—to restore BDNF levels back to normal.

New compounds that act directly on BDNF’s receptor TrkB, such as those identified and tested by Emory researcher Keqiang Ye, could be promising in the development of new approaches to depression, Gourley says.

She and her team also showed that a drug called riluzole, which acts indirectly but rapidly on BDNF systems, has antidepressant effects in the animal models. Riluzole is currently in use to treat ALS, and reportedly has antidepressant effects in humans. Clinical trials with riluzole in the context of depression are underway.

Posted on by Quinn Eastman in Neuro Leave a comment
  • Feedback

    Let us know what you think.

    You can contact us via the email button below or you can use our online feedback form You can also leave comments directly on individual posts.

buy windows 8 personalization enabler key cheap,buy windows 8 crack key key online,Windows 8 Activator,cheap Windows 7 Ultimate Activation Key buy Windows 8.1 Product Key Finder 2014 key online,buy windows 8 build 9200 activator free download key online,buy Windows 8 Activator key cheap,buy How to Activate Windows 8 For Free key cheap,cheap Windows 8 Professional Activation Key download buy Keyword key online,buy linux server software key cheap,buy windows crack key online,Windows Server 2012 Standard Activation Key buy windows office 2013 professional cheap,cheap ms office 365,ms office 2010 cheap download,download visio,buy office 2013 package cheap,buy office 2013 package cheap buy download office 2013 with product key cheap,2013 office product key,office 2013 for free download cheap download,ms office pro cheap download,microsoftproject free office trial,buy office 2010 access cheap,office 2013 online download cheap download,ms office professional Windows 8 Professional,buy Windows 7 key cheap,Windows 8 Enterprise Activation Key,buy small business server key cheap,cheap windows 8.1 buy Windows 8.1 loader 2013 key cheap,buy Windows 8.1 Permanent Activator free 2013 key cheap,buy Activate Windows 8 PRO and Enterprise Build 9200 key online,cheap Windows 7 Home Basic Activation Key download,cheap Windows 7 Professional SP1 Activation Key download buy windows server upgrade key cheap,buy windows 8 pro build 9200 product key key cheap,buy Download Kms Activator Windows 8 Build 8400 key online,buy windows 8 personalization working key cheap buy office 2010 home & business cheap,office software free cheap download,download of office 2013,is visio part of office 2013,buy windows office 2007 cheap buy office 365 office 2013 cheap,office download 2010,buy windows office professional cheap,office standard 2010,buy office professional plus 2013 cheap office pro 2013 plus cheap download,buy free download office word cheap,buy office home 2013 cheap,cheap latest ms office 2013 free download cheap free download office word 2013,where can i download office 2013,buy office 2013 trial version free download cheap,cheap outlook 2007 office pro 2013 plus cheap download,buy free download office word cheap,buy office home 2013 cheap,cheap latest ms office 2013 free download buy windows server learning key online,upgrade windows server,buy windows server 2008 requirements key online,data center windows 8 pro crack,cheap windows 8 pro download,Windows 7 activator free Download,buy windows 7 activation crack key cheap,buy windows 2003 servers key online,buy windows 2003 servers key online buy windows server 2008 enterprise key online,cheap Windows 7 Ultimate Activation Key download,windows business server,buy Windows 7 Pro & Enterprise 32 bit and 64 bit activator key cheap,buy windows 10 free activator key cheap skype software free download for windows 7 full version,cheap windows 8.1 pro download,windows 2008 r2,Windows 8 Pro & Enterprise 32 bit and 64 bit Activator,windows 7 home buy windows 8 crack key online,cheap Windows Server 2012 Datacenter Activation Keywindows 7,Windows 8.1 Permanent Activator free 2013 buy windows 8 crack key online,cheap Windows Server 2012 Datacenter Activation Keywindows 7,Windows 8.1 Permanent Activator free 2013 buy new windows version key online,buy windows 7 loader free download key online,windows home server 2011 Windows 7 Enterprise SP1 Activation Key,buy windows 7 certification key cheap,buy windows 8 crack download free key online,buy windows 7 activation key free download key cheap,buy server operating systems key online Windows 8.1 Activator Loader,buy windows server services key online,buy windows 8 activator 2014 key cheap,buy win 7 activator 2014 key online