Anita Bhattacharyya, PhD—Waisman Center University of Wisconsin at Madison
Creation of an in vivo model for FMR1 reactivation

Anita Bhattacharyya, PhD, Principal Investigator (2006 to Present)
Xinyu Zhao, PhD, Associate Professor (2012 to Present)

FRAXA Awards:

$73,000 in 2013
$73,000 in 2012
$60,000 in 2008
$35,000 in 2007
$30,000 in 2006


One approach for treating Fragile X would be to demethylate the gene and restore expression of FMR1. This can be shown in vitro(cells in the lab), but has yet to be translated into live animals, mostly because the most-widely used mouse model has the gene entirely removed (knocked-out) rather than the CGG repeat which leads to methylation of the gene. Drs. Bhattycharyya and Zhao will transplant human FX induced pluripotent stem cells (iPSCs) into brains of neonatal mice. Then they will use a demethylating agent to assess expression of FMRP. They will also look at genes involved in demethylation and transplant those iPSCs into mouse brains.

Together, these two strategies will provide a new model to test reactivation of the FMR1 gene in mice and will provide a paradigm to screen compounds for reactivating FMR1.
Cyclic AMP Signaling in Fragile X

by Katie Clapp, 2/1/2008

This group studies signaling pathways in fragile X neural stem cells, with a particular interest in abnormalities of cyclic AMP. The use of actual human fragile X cells allows for an examination of the disorder without the inter-species variability encountered in mouse models.

The team has published a paper reporting their findings: The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System, by Daniel J. Kelley, Richard J. Davidson, Jamie L. Elliott, Garet P. Lahvis, Jerry C. P. Yin, and Anita Bhattacharyya.
Defective Cyclic AMP Signaling in Fragile X

Cyclic AMP (cAMP) is a second messenger involved in many brain processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in Fragile X, the most common heritable cause of mental impairment and autism. This team is finding evidence of altered cAMP cascade function in Fragile X and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism with Fragile X from autism per se and the cAMP cascade may be a viable therapeutic target for both Fragile X and autism.

by Anita Bhattacharyya, 4/1/2007

Fragile X syndrome is defined by the loss of fragile X mental retardation protein (FMRP). We are exploring how cellular processes are affected by the loss of FMRP in brain cells, in hopes of identifying pathways to target for potential therapeutics.

Cells respond to signals (e.g. electrical, chemical signals) by signaling cascades that relay information from the outside of the cell to the nucleus where changes in genes occur. We want to test how the loss of FMRP affects a neural cell's signal transduction cascades. One signal transduction relay molecule that has been implicated in Fragile X is cyclic AMP (cAMP). Previous work by Fragile X researcher Elizabeth Berry-Kravis and colleagues showed that cAMP is lower in blood cells from Fragile X individuals. We have found that cells of the nervous system are also not able to produce cAMP as well in Fragile X. Lowered cAMP signal transduction affects how FX cells in the brain respond to stimuli and how they function during development.

In this project, we want to understand why cAMP production is lower in Fragile X. How does the lack of FMRP cause lower cAMP signaling? Is there a link between defective cAMP production and another signal cascade linked to FX, the mGluR pathway? Finally, using a drug assay on human FX cells, we hope to find compounds that can rescue the cAMP defect in Fragile X cells.