Altered Neural Excitability and Chronic Anxiety in a Mouse Model of Fragile X

Altered Neural Excitability and Chronic Anxiety in a Mouse Model of Fragile X

With a $35,000 grant from FRAXA Research Foundation in 2016, Dr. Peter Vanderklish at Scripps Research Institute, and colleagues, explored the basis of anxiety in Fragile X syndrome.

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Which is the right FMRP for Therapeutic Development of Fragile X Syndrome?

Which is the right FMRP for Therapeutic Development of Fragile X Syndrome?

With a 2-year, $90,000 grant from FRAXA Research Foundation over 2016-17, Dr. Samie Jaffrey at Weill Medical College of Cornell University explored which FMRP isoform is the best target to treat Fragile X syndrome.

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Biomarker Discovery and Validation for Fragile X Syndrome

Biomarker Discovery and Validation for Fragile X Syndrome

With a $60,000 grant from FRAXA Research Foundation in 2015 that was renewed in 2016, Dr. Eric Klann of New York University will research biomarkers in fraile X syndrome and how to translate these markers from mouse models to human patients.

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Abnormalities of Synaptic Plasticity in the Fragile X Amygdala

Abnormalities of Synaptic Plasticity in the Fragile X Amygdala

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.

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Fruit Flies to Model and Test Fragile X Treatments

Fruit Flies to Model and Test Fragile X Treatments

Dr. Jongens and his collaborators have found an insulin-like protein in the fly brain that is overexpressed in the Fragile X mutant fly, leading to increased activity of the insulin signaling pathway. Furthermore, they found that certain behavioral patterns in the Fragile X flies can be rescued by expressing the FX gene just in insulin producing neurons in the fly brain. In the mutant, there are other changes in the signaling pathways, including a decrease in cAMP and elevation in PI3K, mTOR, Akt and ERK activity. They now propose to study 2 medicines used for diabetes: pioglitazone (increases cAMP and decreases Akt and ERK) and metformin (inhibits mTOR), in flies and mice to validate the potential efficacy of these novel therapeutics for Fragile X.

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

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

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.

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

Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for 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. Dr. Huber has received $474,300 in grants from FRAXA Research Foundation since then, researching molecular mechanisms and developmental switches in Fragile X syndrome. She has worked with 4 FRAXA Postdoctoral Fellows (Elena Nosyreva, PhD in 2006; Jennifer Roseni, PhD in 2007; Tong Zang, PhD in 2010-2011; and Weirui Guo, PhD in 2012-2013) and has received supporting funds from The Meadows Foundation of/for Texas.

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Serotonergic Rescue of Synaptic Plasticity in FMR1 Knockout Mice

Serotonergic Rescue of Synaptic Plasticity in FMR1 Knockout Mice

With $306,000 in grants from FRAXA Research Foundation, Dr. Julius Zhu from the University of Virginia examined the effects of several drugs such as Buspar and Abilify which manipulate specific serotonin receptors and the effect that has on synaptic plasticity (LTP and LTD).

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Clinical Trials Outcome Measures / Lithium Pilot Trial

Clinical Trials Outcome Measures / Lithium Pilot Trial

With a $281,824 grant from FRAXA Research Foundation from 2002-2011, Dr. Berry-Kravis at the Rush University Medical Center attempted to validate a new automated video tracking system for quantifying physical activity as an outcome measure for Fragile X clinical trials.

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Reactivation of the FMR1 Gene

Reactivation of the FMR1 Gene

With a $172,000 grant from FRAXA Research Foundation from 1999-2010, Dr. Giovanni Neri and his team at Universita Cattolica del S. Cuore screened compounds with Neuropharm (UK) for reactivating compounds. This team is collaborating with Dr. Stephen Haggarty at Harvard and MIT (who also has a FRAXA grant), researching reactivation of the FMR1 gene and characterization of cell lines with unmethylated full mutations. Results published.

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Understanding the Mechanism of mGluR5

Understanding the Mechanism of mGluR5

With a $304,000 grant from FRAXA Research Foundation from 1996-2009, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome, the most recent being a study of spine morphology. Drs. Oostra and deVrij studied miRNA and Fragile X. miRNAs are RNAs that can repress the translation of target mRNAs – therefore they can play a role in protein synthesis within the neuron. Preliminary results showed large differences in miRNA expression in the Fragile X mouse brain compared to the wild type. This lab investigated the effect of mGluR5 antagonists on the levels of these specific miRNAs. Results published.

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Developing Fragile X Treatments in Fruit Flies and Mice

Developing Fragile X Treatments in Fruit Flies and Mice

With a $380,000 grant from FRAXA Research Foundation from 2005-2009, Drs. Sean McBride, Tom Jogens, and Catherine Choi studied one of the most important aspects of FRAXA’s research; the preclinical validation of potential therapeutic strategies. Many labs have found new leads for treatment. However, very few have the capacity to test new drugs in the mouse model to establish efficacy rigorously enough to lead to clinical trials. The McBride lab (in a broad collaboration with the Choi, Jongens, and Skoulakis groups) aims to do just that. Results published.

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Involvement of the miRNA Pathway in Fragile X Syndrome

With a $304,000 grant from FRAXA Research Foundation over several years, Drs. Oostra and deVrij from Erasmus University studied miRNA and Fragile X. miRNAs are RNAs that can repress the translation of target mRNAs – therefore they can play a role in protein synthesis within the neuron. Preliminary results showed large differences in miRNA expression in the Fragile X mouse brain compared to the wild type. This lab investigated the effect of mGluR5 antagonists on the levels of these specific miRNAs.

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Imaging Synaptic Structure and Function in Fragile X Mice

Imaging Synaptic Structure and Function in Fragile X Mice

With in $150,000 grants from FRAXA Research Foundation over 2005-2009, Dr. Carlos Portera-Cailliau studied intact, anesthetized Fragile X mouse brains, looking for defects in the density, length, or dynamics of the dendrites. They looked for changes in the neurons after treatment with mGluR5 antagonists.

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Genome-wide Epigenetic Markers in Fragile X

Genome-wide Epigenetic Markers in Fragile X

With $155,000 in grants from FRAXA Research Foundation over several years, Dr. Miklos Toth of Cornell University discovered increased startle response in Fragile X mice and that baclofen can correct this phenotype. They also studied epigenetics (ie factors other than the gene itself) which can determine symptom severity in Fragile X.

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Basic Mechanisms of Disease and Potential Therapeutic Strategies

Basic Mechanisms of Disease and Potential Therapeutic Strategies

With $245,000 in grants from FRAXA Research Foundation, Dr. Stephen Warren and his lab at Emory University studied all aspects of Fragile X syndrome, from the mechanisms of repeat expansion to high-throughput drug screens in the Drosophila model of Fragile X. The Warren lab made the original discovery of the Fragile X gene, FMR1, in collaboration with the Nelson and Oostra labs, and is recognized internationally as a leader in molecular genetics. Recent projects include establishment of induced pluripotent stem cell lines from Fragile X patients, and determination of other forms of mutation in the Fragile X gene, other than the most common trinucleotide repeat expansion.

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Role of FMRP in the Regulation of Synaptic Plasticity

Role of FMRP in the Regulation of Synaptic Plasticity

With more than $1,000,000 from FRAXA Research Foundation over 13 years, Drs. William Greenough and Ivan-Jeanne Weiler at the University of Illinois uncovered the role of FMRP at synapses, leading to much of the subsequent research on Fragile X syndrome.

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AMPAkines and BDNF in Fragile X: UCI Researchers Restore Memory Process in Fragile X

AMPAkines and BDNF in Fragile X: UCI Researchers Restore Memory Process in Fragile X

With a $104,498 grant from FRAXA Research Foundation from 2003-2008, Dr. Julie Lauterborn at the University of California has done several studies on dentritic spines and finding treatment targets for memory retention in Fragile X mice.

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Regulation of Group I Metabotropic Glutamate Receptor Trafficking in Fragile X

Regulation of Group I Metabotropic Glutamate Receptor Trafficking in Fragile X

With an $83,500 grant from FRAXA Research Foundation in 2005 and 2007, Dr. Anna Fracesconi at Albert Einstein College studied the patterns and pathways of different receptors related to Fragile X.

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Hypothalamic Pituitary Adrenal (HPA) Axis Dysregulation in Fragile X Syndrome

Hypothalamic Pituitary Adrenal (HPA) Axis Dysregulation in Fragile X Syndrome

The hypothalamic pituitary adrenal (HPA) axis is our central stress response system. FRAXA Research Foundation awarded Dr. Carolyn B. Smith $62,000 in funding in 2005 to explore the HPA axis in Fragile X mice. The results of their study indicate that, in FVB/NJ mice, the hormonal response to and recovery from acute stress is unaltered by the lack of Fragile X mental retardation protein. Results published.

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Defining Functional Domains of FMRP and Uncovering its Partners via Large Scale Mutagenesis in Drosophila

Defining Functional Domains of FMRP and Uncovering its Partners via Large Scale Mutagenesis in Drosophila

Yong Zhang, PhD — Chinese Academy of Sciences with Xinda Lin, PhD, FRAXA Postdoctoral Fellow   FRAXA Awards: $40,000 in 2006 $40,000 in 2005   by Xinda Lin FMRP is a widely expressed RNA-binding protein involved in RNA transport and translation. Intensive studies in the last decade have demonstrated that FMRP contains four RNA binding domains, but their actual functions are mostly untested. Meanwhile, a dozen or so protein partners and hundreds of mRNA targets interacting with FMRP have been identified, but again their functions are poorly understood. It is important that the functional domains of FMRP and its interacting partners be identified and characterized in order to understand the pathogenesis of Fragile X. In the last five years, a Drosophila Fragile X model has provided a number of novel insights into FMRP function. Previous work was primarily focused on making null mutations of the gene and then analyzing the

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Experimental Compound FRAX486 Reverses Signs of Fragile X in Mice

Experimental Compound FRAX486 Reverses Signs of Fragile X in Mice

With an $81,000 grant from FRAXA Research Foundation from 2005-2006, Dr. Susumu Tonegawa and his team at MIT studied the enzyme PAK to determine how it could be used for a treatment target. Results published.

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Therapeutic Interventions in FMR1 Knockout and Transgenic Mice: Role of the FMR1 Gene

Therapeutic Interventions in FMR1 Knockout and Transgenic Mice: Role of the FMR1 Gene

With a $229,000 grant from FRAXA Research Foundation in 2006, Drs. Richard Paylor, David Albeck, and Francis Brennan at the Baylor College of Medicine found that, in mice as in humans, the level of Fragile X protein in brain cells plays a prominent role in determining levels of activity and anxiety.

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Splicing Variations of the Fragile X Gene

Splicing Variations of the Fragile X Gene

With an $80,000 grant from FRAXA Research Foundation from 2005-2006, Dr. David Morris and his team at the University of Washington team aimed to understand the variation in distribution and function of FMRP isoforms, sought to identify isoforms of FMRP in mouse brain, and define the expression pattern of these versions of the protein.

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