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Proteome-Scale Investigation of Protein Modification and Metabolic Regulation in Brown Adipose Tissue
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Proteome-Scale Investigation of Protein Modification and Metabolic Regulation in Brown Adipose Tissue. |
| 개인저자 | Entwisle, Samuel W. |
| 단체저자명 | University of Washington. Molecular and Cellular Biology. |
| 발행사항 | [S.l.]: University of Washington., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 102 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781085793643 |
| 학위논문주기 | Thesis (Ph.D.)--University of Washington, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Villen, Judit. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be added to any third party search indexes. |
| 요약 | Brown adipose tissue (BAT) is present in most mammals, and becomes highly metabolically active during cold exposure. Its ability to lower blood glucose and burn calories when it is activated holds great interest for its potential as a therapeutic target for metabolic diseases such as type-2 diabetes. However, in order to leverage this unique functionality of BAT to develop novel therapeutics, it will be important to gain a better systems-wide understand of the cellular consequences of its activation, and the signaling and regulatory networks that control its metabolism. In this dissertation, these questions are explored using mass spectrometry (MS)-based proteomics, through two research projects: a study of protein acetylation and metabolomics in mouse BAT, and a study of signaling dynamics dependent on the mTOR complex 2 subunit RICTOR. To investigate the system-wide molecular effects of different degrees of chronic thermogenesis, we measured protein expression and the levels of protein acetylation using MS, and integrated our analysis with polar metabolite data that had been collected from the same mouse cohort. This analysis uncovered broad increases in mitochondrial protein acetylation after severe cold acclimation, increases to acetylated amino acids and acetylcarnitine, and novel cold-dependent acetylation sites on the uncoupling protein UCP1 that may play a role in regulating protein stability. To investigate the downstream effectors of RICTOR in brown adipocytes, we compared the time course response to insulin of control brown adipocytes and those possessing an inducible knockout of Rictor (Rictor-iKO). We employed MS to measure the global proteome and phosphoproteome, as well as a set of phosphorylation sites in a targeted analysis. This revealed broad differences in the proteome between control and knockout cells including an increased immune response in Rictor-iKO cells, as well as a mild repression of insulin-sensitive sites including the lipogenesis-associated enzyme ATP citrate lyase. These results suggest that RICTOR plays a multifaceted role in cells that extends beyond insulin signaling. In sum, we have investigated the proteome responses to cold acclimation and to the disruption of important signal transduction machinery. The findings have expanded our view of the metabolic flexibility of BAT, and laid the groundwork for future therapeutic strategies to improve BAT function in different contexts. |
| 일반주제명 | Biochemistry. Molecular biology. Endocrinology. |
| 언어 | 영어 |
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