Johns Hopkins School of Medicine

Molecular Mechanism and Experimental Therapeutic of Neurodegenerative Diseases

Over the past 20 years, I have developed two programs in the field of neurodegenerative diseases focused on molecular mechanisms of Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS) and on defining the molecular pathways potentially amenable to therapeutic interventions using molecular biological approaches, including transgenic and gene knockout strategies. Pertinent to this grant application is my research efforts in using mouse models of amyloidosis to validate BACE1 and gamma-secretase, enzymes required for the generation of Abeta, as therapeutic targets for AD. Recently, we have developed a novel mouse model of AD that exhibits amyloidosis and tauopathy which drives neuron loss. Moreover, my group developed a new models of TDP-43 to define the physiological role of this RNA binding protein. We found that TDP-43 serves to repress non-conserved cryptic exons and such function is compromised in brains of neurodegenerative disease.  Our current work is to clarify disease mechanism, validate therapeutic strategy and develop function biomarkers for ALS-FTD, IBM and AD.

Current research projects in the lab include:

1. Characterization of a new family of splicing repressors, including TDP-43, in regulating repression of cryptic exons in the nervous system.

2. Validation of a novel Adeno-associated viral gene therapy to repress splicing of TDP-43 for ALS-FTD.

3. Development of a functional biomarker to monitor cryptic exon incorporation in neurodegenerative disease.

4. Determine whether loss of TDP-43 function contributes to the pathogenesis of AD using a new mouse model that exhibits neuritic plaque dependent tauopathy.