mRNAs Archives • Fragile X Research - FRAXA Research Foundation

Finding Fragile X Biomarkers – From Transcriptomics to Behavior in Patients

FRAXA Research Foundation 2018 Grants • Biomarkers • Carullo, Paulina • Cogram, Patricia • Current Research Grants • Scripps Research Institute • Vanderklish, Peter November 6, 2018January 3, 2019EEG, FRAXA-DVI, mRNAs

With this $20,000 award from FRAXA Research Foundation, Dr. Vanderklish and collaborators at Scripps Research Institute, the University of Chile, and the FLENI Institute in Argentina are analyzing patterns in gene expression in blood cells of patients with Fragile X syndrome. They are using “transcriptomics” which can produce a time-sensitive signature of an individual person. This is the first time that all these different levels of study – from transcriptomics to behavior – have been done for individual patients with Fragile X.

Research Points to Drugs which Inhibit PDE to Treat Fragile X

FRAXA Research Foundation 2016 Grants • 2017 Grants • 2018 Grants • Bardoni, Barbara • Current Research Grants • Disease Mechanisms • INSERM Valbonne, France • Maurin, Thomas • Treatment Targets November 4, 2018November 14, 2018mRNAs, PDE4, Tetra Discovery Partners

FRAXA Research Foundation funded a grant of $90,000 over 2016-2018, for a postdoctoral fellowship for Thomas Maurin, PhD, working under the mentorship of Dr. Barbara Bardoni at INSERM in France. The team works on the biochemistry of the Fragile X protein. They have found that PDE inhibitors (a class of drugs) show promise as treatments for Fragile X syndrome. In related research, FRAXA is currently funding a clinical trial of PDE4D inhibitors.

Novel Modulators of Potassium Channels to Treat Fragile X

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Disease Mechanisms • Kaczmarek, Leonard • Treatment Targets • Yale University December 25, 2017February 6, 2019Autifony Therapeutics, autism, glutamate, hypersensitivity, ion channel, mGluR, mGluR5, mRNAs, potassium channels, sound

With funding from FRAXA over 2015-2017, the Yale University team of Leonard Kaczmarek, PhD showed that the firing patterns of auditory neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop advanced compounds which may reverse these deficits.

In Their Own Words: Reports From the International Fragile X Workshop

FRAXA Research Foundation Cogram, Patricia • Contractor, Anis • Events Recap • Kooy, Frank • Lee, Jeannie • McGill University • Moine, Herve • Razak, Khaleel • Research Updates • Smith, Carolyn B. • Sonenberg, Nahum • Todd, Peter • Vanderklish, Peter October 29, 2017June 18, 2018amygdala, autism, bumetanide, DgkK, EEG, ERK, FDA, Fragile X Meeting, GABA, ganaxolone, glutamate, hyperexcitability, hypersensitivity, metformin, mGluR5, minocycline, mRNAs, Rett syndrome, seizure, sleep, sound

The 18th International Fragile X and Related Neurodevelopmental Disorders Workshop in Quebec, Canada, was a great success, featuring Fragile X much more heavily than any previous meeting in this series! We asked our speakers to summarize their work in their own words. These brief updates from researchers investigating Fragile X.

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

FRAXA Research Foundation 2015 Grants • 2016 Grants • Completed Research Grant • Disease Mechanisms • Geoffroy, Andrea • IGBMC. France • Moine, Herve September 16, 2016April 26, 2018mRNAs

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.

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.

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.

Functional Interplay Between FMRP and CDK5 Signaling

FRAXA Research Foundation Uncategorized April 24, 2014January 24, 2018Alzheimer's, CDK5, GABA, MAP1b, mGluR5, mRNAs

Yue Feng, PhD — Emory University School of Medicine with Wenqi Li, PhD, Postdoctoral Fellow FRAXA Awards: $180,000 $45,000 in 2013 renewed for $45,000 in 2014 $45,000 in 2011 renewed for $45,000 in 2012 Weakened synaptic development and synaptic plasticity, as a result of lacking the functional Fragile X protein (FMRP), underlies the intellectual disability in Fragile X Syndrome (FXS). Decades of investigation established the role of FMRP in binding its mRNA targets and regulating translation in response to neuronal and synaptic activity changes. Exciting discoveries on two receptors, mGluR5 and GABA, signaling in FXS animal models have led to promising therapeutic approaches based on variation of synaptic activity by mGluR5 antagonists and GABA agonists. However, clinical trials only achieved partial reverse of FXS phenotype. Thus, developing additional therapeutic strategies for treating the full spectrum of FXS symptoms are still pressing challenges. The identification of genome-wide Fragile X protein (FMRP) target mRNAs by recent discoveries provides important clues

Fragile X Syndrome Protein Linked to Breast Cancer Progression

FRAXA Research Foundation Bagni, Claudia • Research Updates September 18, 2013June 28, 2018cancer, mRNAs

Having Fragile X Syndrome May Protect Against Breast Cancer Claudia Bagni (VIB/KU Leuven, Belgium, and the University of Rome, Italy) and colleagues have identified the way Fragile X Mental Retardation Protein or FMRP contributes to the progression of breast cancer. The researchers demonstrated that FMRP acts as a master switch controlling the levels of several proteins involved in different stages of aggressive breast cancer, including the invasion of cancer cells into blood vessels and the spread of these cancer cells to other tissues forming metastasis. The work is published online in EMBO Molecular Medicine. The authors identified high levels of FMRP in human breast cancer tissue microarrays and also examined the effects of FMRP levels in a mouse model to study breast cancer. In these mice, high levels of FMRP in primary breast cancer tumors were also linked to the spread of the cancer to the lungs and the developmentRead more

Ab-Mediated Translation in Fragile X Syndrome

FRAXA Research Foundation 2011 Grants • 2012 Grants • Biomarkers • Completed Research Grant • Treatment Targets • University of Wisconsin • Westmark, Cara September 13, 2012April 25, 2018Alzheimer's, LTD (Long-term depression), mGluR, mGluR5, mRNAs

With a $120,000 grant from FRAXA Research Foundation during 2011-2012, Dr. Cara Westmark at the University of Wisconsin explored the role of AbPP as a potential treatment option for fragile X. AbPP produces b-amyloid which is over-expressed in Alzheimer’s disease (AD) and Down 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, 2012August 3, 2018cancer, 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.

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

Role of JNK in FMRP Regulated Translation in Fragile X Syndrome

FRAXA Research Foundation 2011 Grants • 2012 Grants • Completed Research Grant • Disease Mechanisms • Treatment Targets • University of Wisconsin • Wilhelm, Michael January 31, 2012April 25, 2018Alzheimer's, amyloid precursor protein, mGluR, mGluR5, mRNAs

With a $90,000 grant from FRAXA Research Foundation over 2 years, Dr. Michael Wilhelm and his team at the University of Wisconsin studied a protein known as JNK, which is observed to be abnormally regulated in Fragile X. Like FMRP, it is involved in regulating dendritic protein synthesis, and so it may be a target for drug therapy in Fragile X.

Altered Dendritic Synthesis of Postsynaptic Scaffold Protein Shank1 in Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • Completed Research Grant • Disease Mechanisms • Kindler, Stephan • Kreienkamp, Hans-Jurgen • Treatment Targets • University of Hamburg, Germany April 30, 2011April 25, 2018glutamate, mRNAs

With a $106,800 grant from FRAXA Research Foundation over 2 years, Drs. Stephan Kindler and Hans-Jurgen Kreieinkamp studied a protein, Shank1, which is overabundant in Fragile X syndrome.

The Slack Potassium Ion channel is a Therapeutic Target for Fragile X

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • Kaczmarek, Leonard • Treatment Targets • Yale University January 7, 2011January 9, 2019glutamate, mRNAs, potassium channels, sound

With a $282,000 funding from FRAXA Research Foundation, Dr. Leonard Kaczmarek and colleagues explored association of Slack channels with the Fragile X protein (FMRP).

Composition and Localization of Dendritic mRNAs in Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • Stanford University July 9, 2009August 9, 2018autism, mRNAs

With a $80,000 grant from FRAXA Research Foundation over 2 years, Drs. Smith and Wang are investigating which proteins, as well as the mRNA's that code those proteins, are dysregulated in Fragile X. They have developed a elegant system to visualize the proteins and mRNA's and determine where they are spacially in the neuron. This will help to better understand the root causes of Fragile X syndrome and to design targeted treatments. $80,000 Grant Stephen Smith, PhD Principal Investigator Stanford University 2008-2009 FRAXA Research Grant $80,000 over 2 Years A Quantitative Study by Array Tomographic Florescent In Situ Hybridization by Gordon Wang, 8/1/2008 Fragile X syndrome is caused by the malfunction of a fundamental cellular process, the ability of cells to regulate spatially distinct pools of messenger RNA (mRNA). One of the cell types most affected is the neuron. This highly asymmetric cell type relies upon a tightly orchestrated network of proteinsRead more

Understanding the Mechanism of mGluR5 in Fragile X Mouse Models

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • Completed Research Grant • Disease Mechanisms • Erasmus University Rotterdam • Oostra, Ben • Treatment Targets February 26, 2009January 21, 2019AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, TAT (Trans-Activator of Transcription)

With $184,000 in funding from FRAXA Research Foundation from 1996-2005, Dr. Ben Oostra and his team at Erasmus University have done multiple studies related to Fragile X syndrome. This lab created the first Fragile X mouse models and went on to perform many critical studies in Fragile X mouse models. Results published.

Involvement of the miRNA Pathway in Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • de Vrij, Femke • Erasmus University Rotterdam • Oostra, Ben • Research Grant with Results • Treatment Targets February 5, 2009January 21, 2019AFQ056, fenobam, fruit fly, LTD (Long-term depression), mGluR, mGluR5, miRNA, mRNAs, Novartis, prepulse inhibition, prepulse inhibition, TAT (Trans-Activator of Transcription)

With a $120,000 grant from FRAXA Research Foundation over 2008-2009, Drs. Oostra and deVrij at 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.

Basic Mechanisms of Disease and Potential Therapeutic Strategies

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Completed Research Grant • Disease Mechanisms • Emory University • Treatment Targets • Warren, Stephen February 2, 2009April 25, 2018glutamate, iPS, mGluR, mRNAs

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.

Role of FMRP in the Regulation of Synaptic Plasticity

FRAXA Research Foundation 1994-2000 Grants • 2001-2005 Grants • 2006-2010 Grants • Completed Research Grant • Greenough, William • University of Illinois at Urbana-Champaign • Weiler, Ivan Jeanne February 2, 2009April 25, 2018Adeno-associated virus, mRNAs

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.

Effects of Alternative Splicing at FMR1 Exon 15 on Understanding Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • Denman, Robert • Disease Mechanisms • New York State Institute for Basic Research • Treatment Targets February 14, 2008January 14, 2019mRNAs

With a $118,500 grant from FRAXA Research Foundation from 2007-2008, Dr. Robert Denman and his team at the New York State Institute for Basic Research studied protein splicing, specifically looking at exon 15-encoded residues of of FMPR.

Genetic and Behavioral Analyses of the dFMR1 Pathway in Drosophila Peripheral Nervous System

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • Completed Research Grant • Disease Mechanisms • Gao, Fen-Biao • University of California at San Francisco February 13, 2006June 20, 2018fruit fly, mRNAs, sound

With a $160,000 grant from FRAXA Research Foundation from 2004-2006, Dr. Fen-Biao Gao and his team at the University of California studied the relationship between mRNA and FMRP.

Transcriptional Regulation of the Fragile X Gene

FRAXA Research Foundation 2001-2005 Grants • 2006-2010 Grants • Brown University • Completed Research Grant • Disease Mechanisms • Fallon, Justin February 13, 2006January 9, 2019autism, mRNAs

With a $60,000 in grant from FRAXA Research Foundation, Dr. Justin Fallon and his team at Brown University studied systematic mapping of Fragile X granules in developing mouse brains, revealing a potential role for presynaptic FMRP in sensorimotor functions.

Composition and Dynamics of FMRP-Containing RNP Complexes

FRAXA Research Foundation 2001-2005 Grants • Bardoni, Barbara • Disease Mechanisms • INSERM Valbonne, France • Treatment Targets September 20, 2005November 8, 2018mRNAs

FRAXA Research Foundation funded a grant of $30,000 in 2005 to Dr. Barbara Bardoni at INSERM in France. The team works on the biochemistry of the Fragile X protein.

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