Principle Investigator: Falak Sher, Ph.D.

How to translate genetic discoveries into drug development for neurodegenerative diseases?

Genome-wide association studies have identified several susceptibility loci and genetic variants that contribute to the onset of neurodegenerative diseases, e.g., Alzheimer’s disease (AD). However, the translation of genetic findings into drug development is challenging as the underlying complex molecular mechanisms are poorly understood.
Dr. Sher’s lab applies a CRISPR-based functional genomics approach that can identify the functional impact of disease-associated loci/variants and pinpoint the rational DNA/amino acid sequences for developing therapeutic molecules. The lab uses biochemistry, cell biology, and CRISPR-based reverse genetics approaches to test the mechanistic hypothesis in neural (neuron/oligodendrocytes) as well as resident immune cells (microglia) of the brain parenchyma.

Major research questions

• How do AD-associated genetic variants contribute to the assembly of multiprotein complexes? Can we exploit protein-protein interactions for therapeutic modulation of cellular phenotypes (microglia)?
• What are the genetic underpinnings of aberrant vesicular trafficking (endolysosomes) in AD and related dementias?
• How do disease-associated genetic variants in non-coding regions of the genome (promoter/enhancer) contribute to the development of neurodegenerative diseases?
• What are the biochemical and biological roles of sequence-specific transcription/epigenetic factors in neural cell types during health and neurodegeneration?

Ongoing Research Support

• NIA 1R01AG070118 – 01, NIH
• TAME-AD,  Thompson Family Foundation Program for Accelerated Medicines Exploration in Alzheimer’s Disease and Related Disorders of The Nervous System