Joey Nichols

Program: Molecular Genetics and Genomics

Current advisor: Jeffrey Milbrandt, MD, PhD

Undergraduate university: Gonzaga University, 2020

Enrollment year: 2022

Research summary
Neuroinflammation is a major driver of disease. I am investigating novel mechanisms of disease and interactions between inflammatory pathways.

TIR domain-containing proteins are an ancient class of proteins that are conserved across the tree of life. The human genome contains > 30 proteins with annotated TIR domains. Most of these proteins have been understood to function as signaling scaffolds, linking extracellular ligands to intracellular signal cascades. In 2017, the TIR domain of SARM1 was identified as an NAD+ hydrolase activated in response to axon injury. In bacteria and plants, TIR domains also act as NAD+ hydrolases to either deplete cellular NAD+ or produce NAD-derived signaling molecules that activate downstream immune effectors in response to pathogen infection. We hypothesize that more TIR domains in the human genome, beyond SARM1, possess NAD+ hydrolase activity. To test this hypothesis, we are conducting structure-based searches to identify protein domains with structural homology to SARM1 TIR, testing for NAD+ hydrolase activity using in vitro assays and functional genomics approaches. NAD+ is a crucial component of cellular metabolism and its depletion is linked to axon degeneration and diseases of aging. The elucidation of TIRs with NAD+ hydrolase activity will bring a new level of mechanistic understanding to inflammatory and degenerative diseases.

Graduate publications