Kendal Broadie, PhD—Vanderbilt University
Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

Kendal Broadie, PhD, Principal Investigator (2000 to Present)
Cheryl Gatto, PhD, FRAXA Postdoctoral Fellow (2009)
Charles Tessier, PhD, FRAXA Postdoctoral Fellow (2007)
Yong Zhang, PhD, FRAXA Postdoctoral Fellow (2001)

FRAXA Awards:

$78,745 in 2013
$78,745 in 2012
$40,000 in 2009
$40,000 in 2008
$40,000 in 2007
$40,000 in 2006
$35,000 in 2000


Much of the research interest to date in Fragile X has focused on intracellular signaling pathways -- enzyme cascades which translate receptor activation in dendrites into long-lasting effects in neurons. However, it is also know that there are extracellular signaling pathways -- enzyme cascades outside the neuron, which remodel the extracellular matrix, the gelatinous bed in which the neurons exist. Intracellular and extracellular signaling pathways are coupled, and both show abnormalities in Fragile X.

This project aims to understand abnormalities in this lesser-known area outside the brain’s cells; this is especially important because the new Fragile X treatment strategy using minocycline is active here. These pathways are also likely to contain other useful treatment targets.
Studies of Fragile X Neural Function in Drosophila

by Katie Clapp, 2/1/2009

Dr. Broadie's lab uses the fruit fly model to study where in the brain and at what point(s) in development is FMRP needed for normal brain development. In other words, do we need FMRP early in life, as a fetus, young child or budding adolescent, to allow normal brain development and to establish a platform for mature brain functions, or is FMRP more important later, and throughout life, to allow brain circuitry and communication to be adjusted as necessary? The findings from these studies will direct the timing of drug trials and subsequent treatments to enhance efficacy and resolution of Fragile X disease symptoms. Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase
Spatial and temporal requirements of FMRP function in neurological mechanisms: Defining and employing appropriate intervention windows in Fragile X

By Cheryl Gatto and Kendal Broadie, 5/1/2008

To develop any treatment for Fragile X Syndrome (FraX), it is critical to understand the developmental progression of the disease. It remains poorly understood whether FraX is primarily a ‘developmental disease’, reflecting a transient, age-dependent requirement for the Fragile X Mental Retardation Protein (FMRP) in brain development, a ‘plasticity disease’, reflecting a maintained, constant requirement for FMRP in the mature brain, or some two-phase combination of FMRP requirements giving rise to different FraX symptoms. In other words, do we need FMRP early in life, as a fetus, young child or budding adolescent, to allow normal brain development and to establish a platform for mature brain functions, or is FMRP more important later, and throughout life, to allow brain circuitry and communication to be adjusted as necessary? This knowledge is absolutely vital for the design and implementation of any effective FraX interventions, including therapeutic exploitation of the ‘mGluR (metabotropic glutamate receptor) theory of FraX’. We must know when to treat and why.

In the coming year, we will use our well-established Drosophila FraX disease model to dissect the spatial and temporal requirements for FMRP in behavior regulation, brain structure and synaptic function. FMRP expression will be conditionally driven in the brain using the inducible, transgenic system, called the Gene-Switch (GS) method, in animals otherwise completely lacking FMRP. This approach allows FMRP to be turned on throughout the brain, or within specific targeted brain regions, during defined windows of time. This will enable the definition of the critical periods requiring FMRP, and thus therapeutically targetable signaling events, including mGluR signaling. The findings from these studies will direct the timing of drug trials and subsequent treatments to enhance efficacy and resolution of FraX disease symptoms. If we know when to treat and why, we will be able to improve intervention outcomes.
The Drosophila Model of Fragile X: Testing the Metabotropic Glutamate Receptor Hypothesis

By Charles Tessier and Kendal Broadie, 4/1/2007

Over the past 4 years, we have developed a genetic model of Fragile X Syndrome in that best-characterized genetic workhorse system; the fruit fly Drosophila. We previously generated mutant animals lacking or over-expressing the Drosophila Fragile X protein, dFMRP, and demonstrated that mutant animals manifest the characteristic hallmarks of the disease including both neuronal and behavioral defects. An exciting hypothesis suggests that FMRP may be regulated downstream of signaling via metabotropic glutamate receptors (mGluRs). The mGluR theory suggests that FMRP functions to limit neuronal activity in response to these receptors.

We are testing the mGluR theory by using animals that lack both dmGluRA and dFMRP. We are employing physiology and molecular tools to understand the roles of each protein in FXS. We are also using drugs that specifically block mGluR signaling to identify the convergence of these two pathways. This research may lead to new drugs that specifically target molecules involved in the disease and avoid those which may lead to unwanted side-effects.