Most neurodegenerative disorders are marked by the age-dependent accumulation of misfolded and aggregated proteins in the brain, particularly within neurons. Our laboratory seeks to understand how the neuronal protein homeostasis (proteostasis) network defends against age-related neurodegenerative diseases. These diseases include repeat expansion diseases (Huntington's disease, spinocerebellar ataxia, neuronal intranuclear inclusion disease), amyotrophic lateral sclerosis, and frontotemporal lobar degeneration.
We integrate an interdisciplinary approach of high-throughput CRISPR-based functional genomics, transcriptomics, microscopy/imaging, proteomic, and biochemical techniques to study disease mechanisms in cell models (including iPSC-derived neurons), mouse models, and human neuropathologic tissues. We recently developed a highly scalable in vivo pooled CRISPR perturbation system, allowing us to systematically evaluate the role of the neuronal proteostasis network in different disease models and in different neuronal populations.
As we look to build our team, we strongly welcome motivated graduate students and postdoctoral fellows to join our mission in furthering our understanding neurodegeneration.
Research Projects
1. Mapping the neuronal proteostasis network in the Huntington's disease, neuronal intranuclear inclusion disease, and frontotemporal dementia/amyotrophic lateral sclerosis.
2. Understanding the molecular and biochemical/biophysical basis of chaperone selectivity for different disease-associated proteins
3. Dissecting regional and cell-type specific vulnerability in diseases caused by chaperone mutations
4. Elucidating nuclear proteostasis pathways and mechanisms of nuclear proteotoxicity in repeat expansion diseases
5. Defining genetic modifiers and mechanisms of TDP-43-mediated toxicity in aging and neurodegeneration.
We are fortunate to have funding support by the National Institutes of Health and the Larry L. Hillblom Foundation. We are also grateful for the generous donations by individuals and their families that enable us to study their disease directly within their tissues.