My research explores mechanisms used by living cells to control the synthesis and degradation of protein. Specifically, we use stable isotopes to label newly-synthesized molecules with a time-dependent tag. With a mass spectrometer, the time-dependent stable isotope enrichment and relative concentration of many molecules can be measured even within a complex mixture. This allows us to calculate synthesis and degradation rates for many molecules in the body as it responds to stimuli. We have been able to perform experiments that survey synthesis rates broad sections of the proteome, and compare against the synthesis of DNA, RNA or small molecules produced by enzymes within the cell. We have successfully used this technique in many different biosynthetic systems from "cell free" environments to humans. Currently, we are focused on understanding post-transcriptional control of the proteome composition within cells, in particular on the changes associated with aging or disease as well as how protein degradation is regulated to maintain homeostasis. If you find these research questions interesting please come talk to me, I am always open to working with motivated students.
Changes in protein homeostasis associated with aging and disease
A healthy cell very carefully controls the expression and degradation of individual proteins so that the concentration doesn’t change over time. We are studying how changes in cellular control of protein concentration (protein homeostasis) are associated with breast cancer and aging. Our goal is to identify if we can prevent these changes in protein homeostasis. This may allow us to treat cancer and prevent age-associated diseases.
Maintenance of proteome homeostasis through protein degradation
Many of today’s most devastating diseases can be identified as diseases of protein homeostasis. Parkinson’s, Alzheimer’s, Huntington’s, diabetes and other diseases all exhibit cellular deposits of aggregated protein. These aggregates are often highly resistant to degradation and may indicate a dysfunction within the catabolic machinery of the cell. Continuous protein catabolism is critical in the presence of constitutive transcription and translation, yet these processes are poorly understood. It has recently been shown that the cell employs thousands of proteins (ubiquitin ligases, targeted proteases, proteasome, etc.) to guide the process of protein degradation. Thus, the complexity of the regulatory structure for removing a protein from the cell may be comparable to producing the protein in the first place. Our current work is focused on identifying the substrates for cellular proteases and understanding how targeted proteolytic processing is used by the cell.
- Price JC, Khambatta CF, Li KW, Bruss MD, Shankaran M, Dalidd M, Floreani NA, Roberts LS, Turner SM, Holmes WE, and Hellerstein MK, 2012 “The effect of long-term calorie restriction on hepatic proteostasis and mitochondrial dynamics in mice” Mol. Cell. Proteomics, 11.12: 1801-1814
- Price JC, Holmes WE, Li KW, Floreani NA, Neese RA, Turner SM, Hellerstein MK, 2011 “Measurement of human plasma proteome dynamics with 2H2O and liquid chromatography tandem mass spectrometry.” Analytical Biochem., 420(1):73-83
- Price JC, Guan S, Burlingame A, Prusiner SB, Ghaemmaghami S., 2010, “Analysisof proteome dynamics in the mouse brain.” Proc. Natl. Acad. Sci. USA, 107: 14508-13