Global quantification of proteostasis regulation
- Protein homeostasis, or proteostasis, is the result of protein synthesis, folding, degradation, and other quality control mechanisms which work in unison to establish and maintain desired levels of proteins. Deficiencies in proteostasis have been linked to aging and a number of diseases such as Alzheimer's disease, Huntington's disease, and cancer. Although individual mechanisms within the proteostasis network have been studied at length, the extent to which each process is responsible for overall protein maintenance has yet to be uncovered. Genomic and proteomic techniques developed in the last decade and are now capable of measuring proteostasis regulation, particularly protein synthesis and degradation. Chapter 1, the introduction to this dissertation, covers the techniques currently available for studying the dynamics of proteostasis on a systems-level. These techniques were applied in Chapters 2 and 3 to explore proteostasis regulation. Chapter 2 includes a global analysis of four aspects of proteostasis regulation -- transcript abundance, translation, proteins abundance, and degradation. This four dimensional approach to characterizing proteostasis under unperturbed conditions allowed for the detection of several distinct modes of regulation that reflect underlying biological mechanisms notably, non-degradative ubiquitination and mTOR-dependent translation regulation. Expanding our fundamental and quantitative understanding of these and other processes will support future mechanistic studies and will aid in the development of predictive models of proteostasis dynamics. Chapter 3 describes a project, in collaboration with the Kim lab at Stanford, aimed characterizing the aging proteome. Proteostasis collapse has been linked to aging in several of model organisms, however research focused on the systems biology of aging has largely relied on genomic and transcriptomic techniques. Here, we used mass spectrometry to quantify the changes in protein abundance that occur from adulthood to old age in the nematode, C. elegans. We identified over three thousand proteins and reproducibly measured changes in protein abundance for over 60 proteins. Some of these proteins were previously shown to play a role in the aging process, thus supporting our results. Proteins that signify the aging phenotype will serve as candidates for future experiments toward deciphering the mechanisms of aging.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Hinkson, Izumi Vanessa
|Stanford University, Department of Chemical and Systems Biology.
|Kopito, Ron Rieger
|Kopito, Ron Rieger
|Statement of responsibility
|Izumi Vanessa Hinkson.
|Submitted to the Department of Chemical and Systems Biology.
|Thesis (Ph.D.)--Stanford University, 2014.
- © 2014 by Izumi Vanessa Hinkson
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...