Disease Mechanisms Archives • Page 2 of 6 • Fragile X Research

Repurposing Drugs to Dampen Hyperactive Nonsense-Mediated Decay in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Kurosaki, Tatsuaki • Maquat, Lynne • Treatment Targets • University of Rochester September 8, 2016April 19, 2018Boston Bruins Foundation

With a $90,000 grant from the FRAXA Research Foundation, Dr. Lynne Maquat and Dr. Tatsuaki Kurosaki will investigate nonsense-mediated mRNA decay (NMD) in Fragile X. NMD is a “housekeeping” process that cells use to prevent faulty proteins from being made. But there is too much of it in Fragile X syndrome. There are already available drugs that suppress NMD – including caffeine.

Altered Sleep in Fragile X Syndrome: Basis for a Potential Therapeutic Target

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Biomarkers • Current Research Grants • Disease Mechanisms • National Institute of Mental Health • Smith, Carolyn B. • Treatment Targets September 5, 2016January 3, 2019sleep

With a $90,000 grant from FRAXA Research Foundation over 2016-2018, Dr. Carolyn B. Smith and Dr. Rache Sare at the National Institute of Mental Health investigated the basis of sleep problems in Fragile X syndrome.

Abnormalities of Synaptic Plasticity in the Fragile X Amygdala

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • 2015 Grants • 2016 Grants • Chattarji, Sumantra • Completed Research Grant • Disease Mechanisms • National Center for Biological Sciences February 22, 2016August 6, 2018amygdala, autism, mGluR

With a $110,050 grant from FRAXA Research Foundation from 2005-2016, Dr. Sumantra Chattarji at the National Center for Biological Sciences researched how the amygdala is affected by Fragile X syndrome. Results published.

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Completed Research Grant • Disease Mechanisms • Lombroso, Paul • Research Grant with Results • Treatment Targets • Yale University February 26, 2015May 16, 2018AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, STEP (STriatal-Enriched protein tyrosine Phosphatase)

With a $349,000 grant from FRAXA Research Foundation from 2008-2015, Dr. Paul Lombroso and his team at Yale University researched if inhibiting STEP could reduce behavioral abnormalities in Fragile X syndrome. Results published.

Molecular Mechanisms of Cytoskeletal Regulation by FMRP

FRAXA Research Foundation 2015 Grants • Cornell University • Disease Mechanisms • Jaffrey, Samie • Treatment Targets January 9, 2015January 9, 2019

With a 2-year, $120,000 grant from FRAXA Research Foundation in 2015, Dr. Samie Jaffrey from Weill Medical College of Cornell University will research the connection between FMR1, RhoA, and dendritic spine abnormalities.

GABA-A Receptor in Fragile X Syndrome

Katie Clapp 1994-2000 Grants • 2006-2010 Grants • Completed Research Grant • Disease Mechanisms • Kooy, Frank • University of Antwerp, Belgium October 19, 2014January 23, 2019GABA, GABA-A, sleep

With $210,000 in grants from FRAXA over 1999-2010, Dr. Frank Kooy has studied the involvement of the GABAergic system in Fragile X syndrome, at the University of Antwerp, Belgium.

Cellular-Specific Therapeutic Targeting of Inhibitory Circuits in Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • 2014 Grants • Cea-Del Rio, Christian • Completed Research Grant • Disease Mechanisms • Huntsman, Molly • Treatment Targets • University of Colorado September 13, 2014April 25, 2018endocannabinoid, glutamate, mGluR, seizure, somatostatin

Studies have shown that the function of inhibitory networks is disturbed in Fragile X. This abnormality is not well understood but appears to be secondary to abnormalities in metabotropic glutamate and endocannabinoid systems. With a $90,000 grant from FRAXA in 2013-2014, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.

Functional Interplay Between FMRP and CDK5 Signaling

FRAXA Research Foundation 2011 Grants • 2012 Grants • 2013 Grants • 2014 Grants • Biomarkers • Completed Research Grant • Disease Mechanisms • Emory University • Feng, Yue • Li, Wenqi • Treatment Targets September 13, 2014April 25, 2018Alzheimer's, CDK5, GABA, MAP1b, mGluR5, mRNAs

With a $180,000 grant from the FRAXA Research Foundation over 2011-2014, Dr. Yue Feng and Dr. Wenqi Li at Emory University will study CDK5 pathway function and regulation in an effort to break down whether and how CDK5 signaling is affected by the loss of the Fragile X protein, FMRP, in the Fragile X mouse model.

Computational Analysis of Neural Circuit Disruption in Fragile X Model Mice

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • FRAXA Research Grants • O’Donnell, Cian • Salk Institute • Sejnowski, Terrence September 12, 2014April 25, 2018

Computer modeling of the brain offers the hope of predicting how the brain responds to varying conditions, but these models have been rather primitive until recently. The Sejnowski team at the Salk Institute, who specialize in computational models of neural networks, will take the results of previous FRAXA-funded projects and incorporate them into their advanced computer models of brain function.

Synaptic Characterization of Human Fragile X Neurons

FRAXA Research Foundation 2013 Grants • 2014 Grants • Disease Mechanisms • FRAXA Research Grants • Marro, Samuele • Research Grant with Results • Stanford University • Treatment Targets • Wernig, Marius September 12, 2014March 27, 2019Retinoic Acid Signaling

With a $90,000 grant from FRAXA Research Foundation over 2013-14, Dr. Marius Wernig and Dr. Samuele Marro at Stanford analyzed homeostatic plasticity and regulation of synaptic strength by retinoic acid. If the results are encouraging, they will move forward with testing whether available RA antagonists can alleviate observed abnormalities in these cells.

Bcl-xL Inhibition as a Therapeutic Strategy for Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • FRAXA Research Grants • Jonas, Elizabeth • Levy, Richard • Treatment Targets • Yale University September 12, 2014April 25, 2018autism

Scientists have found increases in the numbers of neurons in brain regions of autistic children, suggesting a problem in developmental programmed cell death pathways. One of the most important effectors of neuronal survival during brain development is the “anti-cell death” protein Bcl-xL. While the normal function of Bcl-xL is to maintain a healthy number of neurons and synapses, over-expressed Bcl-xL can cause an overabundance of synaptic connections. This may be happening in Fragile X.

Seizures in Fragile X Syndrome and Therapeutic Potential of NMDA Receptor Antagonists

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • Drug Repurposing • State University of New York • Treatment Targets • Wong, Robert September 8, 2014April 28, 2018autism, glutamate, mGluR, NMDA, seizure

With a $90,000 grant from the FRAXA Research Foundation, Dr. Robert Wong is investigating how seizures are generated in Fragile X neurons. More generally, he is looking at how synapses are modified to enable learning and memory and how this process is impaired in Fragile X. $90,000 Grant Robert Wong, PhD Principal Investigator State University of New York 2013-2014 FRAXA Research Grant $90,000 over 2 Years Abnormal increases in sensitivity of a type of glutamate receptor (group I mGluR) cause brain malfunction, including epilepsy, in Fragile X syndrome (FXS). We are examining a newly uncovered regulation of this increased group I mGluR sensitivity by a second type of glutamate receptor, the NMDA receptor. By looking at audiogenic seizures in FXS model mice, NMDA receptor blockers were found to robustly suppress these seizures at the young developmental stage. In contrast, the same antagonists activated seizure activities, normally dormant, in adult FXS model mice and in a CGGRead more

Translation-Independent Functions of FMRP in Excitability, Synaptic Transmission and Plasticity

FRAXA Research Foundation 2012 Grants • 2013 Grants • Completed Research Grant • Deng, Pan-Yue • Disease Mechanisms • Klyachko, Vitaly • Rotman, Ziv • Treatment Targets • Washington University September 12, 2013August 6, 2018

With a $140,000 grant from FRAXA Research Foundation, Dr. Vitaly Klyachko and team at Washington University explored STP (short-term plasticity) in Fragile X, namely looking at presynaptic calcium dynamics as a major underlying cause of the STP defects.

Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

FRAXA Research Foundation 2012 Grants • 2013 Grants • Broadie, Kendal • Completed Research Grant • Disease Mechanisms • Drug Repurposing • Gatto, Cheryl • Treatment Targets • Vanderbilt University September 2, 2013April 25, 2018fruit fly, matrix metalloproteinase, minocycline, RNAi

With a $157,000 grant from the FRAXA Research Foundation in 201202013, Dr. Kendal Broadie and Dr. Cheryl Gatto worked to define the distinct but also overlapping roles for MMP-1 and MMP-2 in synaptic structural and functional development. In drug studies with Fragile X fruit flies, they will be testing a range of MMPIs in drug treatments to compare effectiveness during development and at maturity, in order to define the contributions of FXS developmental impairments and adult recovery/plasticity.

Endocannabinoid Mediated Synaptic Plasticity in Fragile X Mice

FRAXA Research Foundation 2006-2010 Grants • 2012 Grants • 2013 Grants • Biomarkers • Completed Research Grant • Disease Mechanisms • ISERM Marseille, France • Manzoni, Olivier • Research • Researcher • Treatment Targets June 2, 2013May 16, 2018endocannabinoid, mGluR, mGluR5

With a $90,000 grant from FRAXA Research Foundation over two years, Drs. Olivier Manzoni and Daniela Neuhofer researched the relationship between Fragile X syndrome and the areas of the brain that are involved in reward processing, regulation of emotional behavior and emotional memory as well as attention, planning and working memory.

Is There a Developmental Switch in the Effects of FMRP?

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • 2011 Grants • 2012 Grants • Completed Research Grant • Disease Mechanisms • Huber, Kimberly • University of Texas at Southwestern March 12, 2013January 21, 2019glutamate, mGluR, mGluR5

With a $474,300 grant from FRAXA Research Foundation from 2000-2013, Dr. Kimberly Huber and her team at the University of Texas conducted several studies on the relationship between mGluR5 and Fragile X syndrome. Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000.

Preclinical Evaluation of Serotonin Receptor Agonists as Novel Pharmacological Tools in Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • Ciranna, Lucia • Completed Research Grant • Disease Mechanisms • Treatment Targets • Universita di Catania, Italy February 22, 2013August 9, 2018glutamate, LTD (Long-term depression), mGluR, seizure, serotonin

With a $66,000 grant from FRAXA Research Foundation in 2013, Dr. Lucia Ciranna and her team from the Universita di Catania tested if specific serotonins could reverse abnormal phentotypes found in Fragile X syndrome.

The Endocannabinoid System in a Mouse Model of Fragile X Syndrome

FRAXA Research Foundation 2011 Grants • 2012 Grants • 2013 Grants • Alger, Bradley • Completed Research Grant • Disease Mechanisms • Treatment Targets • University of Maryland February 1, 2013January 9, 2019autism, endocannabinoid, GABA, glutamate, hyperexcitability, seizure

With a $128,500 grant over 2011-2013 from FRAXA Research Foundation, Drs. Bradley Alger and and Ai-Hui Tang at the University of Maryland researched endocannabinoid pathways in Fragile X.

Small Rho GTPases, a Potential Therapeutic Target for Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • 2013 Grants • Completed Research Grant • Disease Mechanisms • Tejada-Simons, MariVi • Treatment Targets • University of Houston January 30, 2013August 9, 2018glutamate, lovastatin, mGluR, mGluR5, Rac1

With $384,345 in grants from FRAXA Research Foundation, Dr. MariVi Tejada from the University of Houston focused on a particularly promising point of intervention in pathways of brain receptors, and tested several potential therapeutic compounds in an attempt to rescue function in the mouse model of Fragile X.

Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

FRAXA Research Foundation 2012 Grants • 2013 Grants • Completed Research Grant • Disease Mechanisms • Huber, Kimberly • Research • Researcher • Treatment Targets • University of Texas at Southwestern January 30, 2013January 21, 2019glutamate, mGluR, mGluR5

With a $90,000 grant from FRAXA Research Foundation, Dr. Kimberly Huber and Dr. Weirui Guo at the University of Texas at Soutnwestern investigated the roles of Homer and CaMKII in Fragile X syndrome.

Synaptic Actin Signaling Pathways in Fragile X

FRAXA Research Foundation 2006-2010 Grants • 2012 Grants • Completed Research Grant • Disease Mechanisms • Duke University • FRAXA Research Grants • Kim, Hwan • Soderling, Scott September 11, 2012April 25, 2018CYFIP, mGluR, mRNAs, PAK (p21-activated kinase)

With a $163,356 grant from FRAXA Research Foundation in 2010-12, Dr. Scott Soderling and Dr. Hwan Kim at Duke University bred the standard mouse model of Fragile X syndrome to their lines of mice that express reduced levels of several key proteins that modulate synaptic actin. These compound mutant mice were compared to FXS mice to determine if genetically impairing pathways to the actin cytoskeleton can rescue deficits in the FXS mice.

Genetic and Pharmacologic Manipulation of PI3K Activity in FXS: Assessing Potential Therapeutic Value

FRAXA Research Foundation 2011 Grants • 2012 Grants • Bassell, Gary • Completed Research Grant • Disease Mechanisms • Emory University • FRAXA Research Grants • Gross, Christina • Muddashetty, Ravi • Treatment Targets September 2, 2012February 22, 2019cancer, mRNAs, mTOR

With a $90,000 grant from the FRAXA Research Foundation, Dr. Gary Bassell and his team at Emory University explored the PI3K/mTOR signaling complex in FXS via genetic and pharmacologic rescue approaches, to reduce the enzymatic function of specific components of this complex pathway in an FXS mouse model.

Reward Function in Fragile X Syndrome

FRAXA Research Foundation 2011 Grants • 2012 Grants • Completed Research Grant • Cowan, Christopher • Disease Mechanisms • Mclean Hospital • Smith, Laura N. September 2, 2012April 25, 2018autism, dopamine, hypersensitivity, mGluR5

With a $82,500 grant from FRAXA Research Foundation in 2011-2012, Dr. Christopher Cowan and Dr. Laura Smith explored the role of specific signaling pathways in drug-related behavioral deficits, including determining the role, if any, of known impairments in the Fragile X brain.

Inherited Channelopathies in Cortical Circuits of Fmr1 KO Mice

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • Completed Research Grant • Disease Mechanisms • Frick, Andreas • Neurocentre Magendie, France • Treatment Targets August 22, 2012January 9, 2019autism, channelopathy, hypersensitivity, ion channel, mRNAs

With this $90,000 award, Dr. Zhang and Principal Investigator Dr. Andreas Frick at Neurocentre Magendie in France investigated channelopathies using Fragile X mice. $90,000 GrantAndreas Frick, PhD Principal Investigator Yu Zhang, PhD FRAXA Postdoctoral Fellow Neurocentre Magendie 2010-11 FRAXA Research Grant $90,000 over 2 Years Many other proteins are misregulated as a result of the absence of FMRP. It is known that many ion channels, the pores in the cell membrane which allow neurons to conduct electrical impulses, have altered levels in Fragile X. This state is sometime called a “channelopathy” in the pharma world. This group is studying the effect of specific alterations in ion channels, and potential therapeutic effects of drugs which open and close these channels. The mammalian neocortex is central for processes as diverse as sensory information processing, perception or control of motor activity, and cortical defects have devastating neurological and psychiatric consequences. In humans, the consequencesRead more

In Vitro Coherent Network Activity

FRAXA Research Foundation 2011 Grants • 2012 Grants • Bacigalupo, Juan • Completed Research Grant • Disease Mechanisms • University of Chile February 22, 2012April 25, 2018

With a $90,000 grant from FRAXA Research Foundation from 2011-2012, Dr. Juan Bacigalupo at the University of Chile studied the abnormal network dynamics of the brain in Fragile X mice to provide information for future therapeutic drug screening.