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

Fragile X Nervous (System) Breakdown

Theodore Coutilish Disease Mechanisms • Research Updates March 21, 2017June 14, 2018drug repurposing, mRNAs, Roche

“The occurrence and development of events by chance in a happy or beneficial way.” That’s how Lynne E. Maquat, PhD, describes the process of how her research extended to Fragile X syndrome to better understand it and ultimately find advanced treatments.

Fragile X Research Tackles High Anxiety – Peter Vanderklish

Theodore Coutilish Disease Mechanisms • Research Updates • Scripps Research Institute • Treatment Targets • Vanderklish, Peter February 9, 2017July 26, 2018hypersensitivity

Yes, we all know the signs of Fragile X anxiety: Ears begin turning red followed by incessant pacing, heavy breathing, stiffening body, flapping, jumping, avoidance or yelling. Sometimes, it’s the more severe screaming, pinching, scratching, biting and general tearing things up or, worse, the nuclear meltdown.

Function of FMRP and Test of a Novel Therapeutic Approach in a Fragile X Mouse Model

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Geoffroy, Andrea • IGBMC. France • Moine, Herve • Research Grant Results September 16, 2016March 28, 2019DgkK, mRNAs

With a 2015-2016 $90,000 grant from FRAXA Research Foundation, Dr. Herve Moine and Dr. Andrea Geoffroy aim to uncover the exact role of FMRP and to test a novel possible means to correct for FMRP absence in the mouse model of Fragile X syndrome.

Correcting Defects in Astrocyte Signaling in Fragile X Syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Doering, Laurie • McMaster University, Canada • Research Grant Results • Scott, Angela • Treatment Targets September 14, 2016February 25, 2020astrocytes, NIH

With a $90,000 grant from the FRAXA Research Foundation from 2015-2016, Dr. Laurie Doering and Dr. Angela Scott at McMasters University studied astrocytes in Fragile X. Astrocytes, brain cells which support neurons, do not transmit signals. Several treatment strategies for Fragile X have been proposed based on correction of “astrocyte phenotypes”.

Fragile X Mutant Mouse Models

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2012 Grants • 2014 Grants • 2015 Grants • 2016 Grants • Baylor College of Medicine • Disease Mechanisms • Nelson, David September 10, 2016July 26, 2022FXTAS, mRNAs

With $375,000 in grants from the FRAXA Research Foundation since 2009, Dr. David Nelson has developed an impressive array of advanced mouse models of Fragile X, at Baylor College of Medicine. These models are available to investigators worldwide on request. This resource has been essential for a broad, rapid distribution of Fragile X and related gene mouse models and has increased the pace of Fragile X research.

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

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Drug Repurposing • Kurosaki, Tatsuaki • Maquat, Lynne • Research Grant Results • Treatment Targets • University of Rochester September 8, 2016February 11, 2021Boston Bruins Foundation, mRNAs, NIH, Roche

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 • Completed Research Grants • Disease Mechanisms • National Institute of Mental Health • Smith, Carolyn B. • Treatment Targets September 5, 2016May 14, 2020NIH, sleep

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 • Disease Mechanisms • National Center for Biological Sciences • Research Grant Results February 22, 2016June 29, 2021amygdala, autism, mGluR, NIH

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.

FRAXA Grant to Nahum Sonenberg, PhD — Effects of metformin in Fmr1 knockout mouse model of Fragile X syndrome

FRAXA Research Foundation 2015 Grants • 2016 Grants • Disease Mechanisms • Drug Repurposing • McGill University • Research Grant Results • Sonenberg, Nahum • Treatment Targets April 8, 2015May 15, 2020AMPK, FDA, metformin, mRNAs, mTOR

Mis-regulation of activity-dependent protein synthesis is one of the major cellular abnormalities found in Fragile X. Upstream neuronal signaling regulates a large cluster of enzymes called the mTORC1 complex, which in turn regulates protein synthesis. This complex is also controlled by cellular energy levels via the metabolic sensor AMP-activated Protein Kinase (AMPK). AMPK is a highly conserved kinase that is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases.

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Disease Mechanisms • Lombroso, Paul • Research Grant Results • Treatment Targets • Yale University February 26, 2015May 17, 2020AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, NIH, seizure, 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 • Completed Research Grants • Cornell University • Disease Mechanisms • Jaffrey, Samie • Treatment Targets January 9, 2015December 4, 2019mRNAs

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 Grants • 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 • Disease Mechanisms • Huntsman, Molly • Research Grant Results • Treatment Targets • University of Colorado September 13, 2014May 25, 2020CBD, endocannabinoid, glutamate, mGluR, NIH, 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 • Disease Mechanisms • Emory University • Feng, Yue • Li, Wenqi • Research Grant Results • Treatment Targets September 13, 2014June 29, 2020Alzheimer's, CDK5, GABA, MAP1b, mGluR5, mRNAs, NIH

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 • Disease Mechanisms • FRAXA Research Grants • O’Donnell, Cian • Research Grant Results • Salk Institute • Sejnowski, Terrence September 12, 2014May 28, 2020neural network, NIH, sleep

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 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 • Disease Mechanisms • FRAXA Research Grants • Jonas, Elizabeth • Levy, Richard • Research Grant Results • Treatment Targets • Yale University September 12, 2014September 18, 2020autism

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 Grants • Disease Mechanisms • Drug Repurposing • State University of New York • Treatment Targets • Wong, Robert September 8, 2014December 13, 2019autism, 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.

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

FRAXA Research Foundation 2012 Grants • 2013 Grants • Deng, Pan-Yue • Disease Mechanisms • Klyachko, Vitaly • Research Grant Results • Rotman, Ziv • Treatment Targets • Washington University September 12, 2013December 19, 2019BK channel, mGluR, NIH

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 • Disease Mechanisms • Drug Repurposing • Gatto, Cheryl • Research Grant Results • Treatment Targets • Vanderbilt University September 2, 2013May 21, 2020fruit fly, matrix metalloproteinase, minocycline, NIH, RNAi

With a $157,000 grant from the FRAXA Research Foundation in 2012-2013, 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 • Disease Mechanisms • ISERM Marseille, France • Manzoni, Olivier • Research • Research Grant Results • Researcher • Treatment Targets June 2, 2013November 12, 2019CBD, endocannabinoid, mGluR, mGluR5, NIH

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.

Research Grants to Dr. Kimberly Huber 2000-2010

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Completed Research Grants • Disease Mechanisms • Huber, Kimberly • University of Texas at Southwestern March 12, 2013September 19, 2019mGluR, 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 • Disease Mechanisms • Research Grant Results • Treatment Targets • Universita di Catania, Italy February 22, 2013February 3, 2020glutamate, LTD (Long-term depression), mGluR, NIH, 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 • Disease Mechanisms • Research Grant Results • Treatment Targets • University of Maryland February 1, 2013January 29, 2020autism, CBD, endocannabinoid, GABA, glutamate, hyperexcitability, NIH, seizure

With a $128,500 grant over 2011-2013 from FRAXA Research Foundation, Drs. Bradley Alger 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 • Disease Mechanisms • Research Grant Results • Tejada-Simons, MariVi • Treatment Targets • University of Houston January 30, 2013May 18, 2020glutamate, lovastatin, mGluR, mGluR5, NIH, 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.