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Targeted Genetic Screens Identify Metabolic Regulators of T Helper Cell Differentiation and Function
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Targeted Genetic Screens Identify Metabolic Regulators of T Helper Cell Differentiation and Function. |
| 개인저자 | Shyer, Justin Andrew. |
| 단체저자명 | Yale University. Immunobiology. |
| 발행사항 | [S.l.]: Yale University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 130 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781088320310 |
| 학위논문주기 | Thesis (Ph.D.)--Yale University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Craft, Joseph E. |
| 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 | Upon activation, CD4 T cells exhibit changes in cellular metabolism required to meet the bioenergetic, biosynthetic, and functional demands of an effector T cell. Activating signals, including TCR crosslinking, co-stimulation, and cytokine signaling converge on master metabolic regulators whose activity orchestrate cellular biochemistry. Unlike their naive counterparts, activated CD4 T cells engage a program of anabolism, favoring the production of substrates required for cell division and remodeling over more efficient cellular bioenergetic processes. This anabolic program is an absolute requirement for the activation of CD4 T cells, but how the cellular biochemical state regulates CD4 T cell activation processes is incompletely understood.Herein, I first present a broad introduction to CD4 T cell activation and metabolism in Chapter 1. In chapter 2, I describe the development and validation of multiple novel tools for conducting CRISPR/Cas9 screens in primary murine cells. I describe the application of these tools in Chapter 3, in which I present the results of a metabolic gene targeted CRISPR/Cas9 screen conducted in murine primary Th1 cells in vitro. I describe both the success of the screen in identifying known metabolic regulators of Th1 cell activation, as well as the novel discovery that the citrate acid (TCA) cycle and components of the electron transport chain (ETC) are required for Ifng transcription in our model. This discovery is further explored in Chapter 4, in which we use genetic, pharmacologic, and metabolomic approaches to demonstrate that early Th cell differentiation processes, including proliferation and epigenetic remodeling, are uncoupled from late Th cell effector function by TCA cycle metabolite utilization. I describe our finding that early in activation, Th1 cells require a set of mitochondrial transporters to shuttle metabolites, including citrate and aspartate, from the mitochondria for consumption in the cytoplasm to promote cell division and epigenetic remodeling. This is opposed to cells late in activation, which require the activity of Complex II of the ETC (succinate dehydrogenase |
| 일반주제명 | Immunology. |
| 언어 | 영어 |
| 바로가기 | 
: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
