Current Projects

Global analysis of protein homeostasis

A central focus of the lab is the development of novel mass spectrometry-based methodologies for system-wide analyses of protein homeostasis. Specifically, we are developing novel techniques for measuring the kinetics of protein degradation, folding, stability and oxidation on proteome-wide scales. These projects are being conducted in collaboration with the University of Rochester Mass Spectrometry Resource Laboratory.

Selected Publications:
"Quantitative analysis of in vivo methionine oxidation of the human proteome." J Proteome Res. 2020
"Global analysis of methionine oxidation provides a census of folding stabilities for the human proteome." Proc Natl Acad Sci 2019
"Time-resolved analysis of proteome dynamics by TMT-SILAC hyperplexing." Mol Cell Proteomics 2016

Proteostatic response to quiescence

In propagating cells, long-lived intracellular proteins are cleared primarily by the diluting effects of cell division. As a result, when propagating cells stop dividing and enter quiescence, long-lived proteins have a tendency to accumulate in the cell. We have discovered that cells counter this global proteostatic disruption by activating the macroautophagy pathway and increasing lysosomal biogenesis. We are currently in the process of uncovering the cellular pathways that link quiescence to macroautophagy.

Selected Publications:
"Global analysis of cellular protein flux quantifies the selectivity of basal autophagy." Cell Rep. 2016
"Proteome-wide modulation of degradation dynamics in response to growth arrest." PNAS 2017

Protein turnover and aging

We are actively investigating the relationship between protein turnover and aging. By conducting analyses of proteome turnover kinetics across multiple species, we have observed a negative correlation between protein turnover rates and maximum lifespan. We have hypothesized that by reducing the energetic demands of continuous protein turnover, long-lived species may have evolved to reduce the generation of reactive oxygen species and the corresponding oxidative damage over their extended lifespans. We are currently conducting experiments to test this hypothesis and further investigate the link between protein homeostasis and aging.

Selected Publications:
"Cross-species comparison of proteome turnover kinetics." Mol Cell Proteomics 2018
"Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands." bioRxiv 2020

The toxicity of prion aggregates

Accumulation of protein aggregates are generally toxic to cells. Yet, the exact mechanism of toxicity for many types of protein aggregates remain incompletely understood. We are investigating the toxic mechanism of prion protein aggregates that accumulate during the course of prion diseases such as Creutzfeldt Jakob Disease. These aggregates tend to accumulate in the endocytic pathway within prion infected cells and are highly toxic to neurons. Yet, many other cell types (e.g. neuroblastomas) can accumulate prion aggregates without any signs of overt toxicity. Our lab is trying to uncover the exact cellular mechanisms that make some cells resistant to the toxic effects of prions.

Selected Publication:
"Global analysis of protein degradation in prion infected cells." Sci. Rep. 2020