Mechanisms and functions of fatty acid oxidation in T cell differentiation

T细胞分化中脂肪酸氧化的机制和功能

• 批准号: 10540296
• 负责人: Jianhua Xiong
• 金额: $ 24.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540296
• 关键词: ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acetylation; Acids; Advisory Committees; Affect; Applications Grants; Autoimmune Diseases; Biochemical; Bioenergetics; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candidate Disease Gene; Carnitine Palmitoyltransferase I; Catabolic Process; Cell physiology; Cells; Cellular Immunity; Cellular biology; Central Nervous System; ChIP-seq; Chemicals; Citrates; Citric Acid Cycle; Collaborations; Communication; Core Facility; Cytosol; Data; Development; Development Plans; Disease; Disease model; Endothelial Cells; Endothelium; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Experimental Autoimmune Encephalomyelitis; Extramural Activities; Fatty Acids; Fellowship; Flow Cytometry; Foundations; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Transcription; Genomics; Genus Hippocampus; Goals; Grant; Histone Acetylation; Histone H3; Histopathology; Homeostasis; Immune; Immunology; In Vitro; Infection; Inflammatory; Institution; Intraperitoneal Injections; Job Application; K-Series Research Career Programs; Knockout Mice; Knowledge; Learning; Lesion; Lysine; Malignant Neoplasms; Measures; Mediation; Meninges; Mentors; Mentorship; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Molecular; Mus; National Heart, Lung, and Blood Institute; Oral; Oxygen Consumption; Pathway interactions; Positioning Attribute; Postdoctoral Fellow; Process; Professional Competence; Protein Acetylation; Protein Isoforms; Proteins; Proteomics; Public Health; Publications; Research; Research Training; Role; Scientist; Secure; Signal Transduction; Site; Solid; T cell differentiation; T cell infiltration; T cell regulation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Training; Transducers; Tricarboxylic Acids; United States National Institutes of Health; Work; Writing; academic preparation; career development; citrate carrier; conditional knockout; cost; cytokine; etomoxir; experience; extracellular; fatty acid oxidation; in vivo; inhibitor; insight; interest; long chain fatty acid; metabolic abnormality assessment; metabolic phenotype; mouse model; next generation sequencing; non-histone protein; novel; oxidation; pharmacologic; skills; tenure track; transcriptome sequencing; translational applications; translational potential

Project Summary/Abstract Through this K22 Career Development Award proposal, I seek further mentored research training while developing career skills to facilitate a successful transition to research independence. Therefore, this proposed plan is tailored to extend beyond my skillset developed during my postdoctoral fellowship at the NHLBI beyond metabolic studies and into immunology. This proposal takes advantage of the outstanding scientific environment in my mentor’s lab and at the NHLBI to learn new techniques, including next-generation sequencing analysis, advanced flow cytometry, histopathology, and proteomics. To train in these methods and assist with the research aims, I have established collaborations with other labs and several NHLBI core facilities. Furthermore, a career development plan is included to ensure thorough preparation for an academic position by cultivating my oral and written communication, mentorship, and lab management. Advisory Committee has been assembled consisting of my primary mentor and several other prominent scientists, who not only have extensive scientific experience in fields related to the T cell biology and cellular metabolism, which are proposed in this grant, but have also committed to guiding presentations, job applications, and negotiation strategies. This training will help me to secure a tenure-track position at an extramural institution. The research goal of this proposal is to dissect the roles (Aim 1) and the detailed mechanisms (Aim 2) of mitochondrial fatty acid β-oxidation (FAO) in CD4 T cell differentiation and functions and to further evaluate the translational applications of altering FAO levels in T cells (Aim 3). T cells are central to cell-mediated immunity. The dysregulation of T cell differentiation and related functions leads to a variety of immune-related diseases, such as cancer, infections, and autoimmune and inflammatory diseases. The differentiation of T cell subsets is associated with metabolic rewiring. Metabolic rewiring is a bioenergetic adaptation to different conditions and a hallmark of T cell differentiation is FAO, a major catabolic process that degrades long-chain fatty acids. I have recently generated conditional knockout mice with an endothelial FAO deficiency, and have demonstrated that FAO is a critical regulator of endothelial cell fates both in vitro and in vivo. Another genetic mouse model with a T-cell-specific FAO deficiency has also been produced. Using this novel model, combined with cutting-edge biochemical techniques, I seek to fill the gap in our knowledge of the molecular basis of FAO in the regulation of T cell differentiation and related functions (Aims 1 and 2). Furthermore, the goal of Aim 3 is to evaluate the translational potential of altering FAO levels in T-cell-associated disease models. This proposal is of profound significance because, by answering the fundamental questions of how FAO controls T cell differentiation and functions, it will lay a solid foundation for the development of new metabolic-based therapeutic approaches for a wide range of immune-related diseases. Upon transition to independence, the findings from the proposed research will be used to prepare an NIH R01 grant application.

项目总结/摘要 通过这个K22职业发展奖提案，我寻求进一步的指导研究培训， 发展职业技能，以促进成功过渡到研究独立。因此，本建议 计划是量身定制的，以扩展我在NHLBI博士后研究期间开发的技能， 代谢研究和免疫学。这项建议利用了杰出的科学环境 在我导师的实验室和NHLBI学习新技术，包括下一代测序分析， 先进的流式细胞术、组织病理学和蛋白质组学。培训这些方法并协助研究 为了实现这一目标，我已经与其他实验室和几个NHLBI核心设施建立了合作关系。此外，职业生涯 包括发展计划，以确保通过培养我的口语和 书面交流、指导和实验室管理。咨询委员会由以下人员组成 我的主要导师和其他几位杰出的科学家，他们不仅有丰富的科学经验， 在与T细胞生物学和细胞代谢相关的领域，这是在这个补助金中提出的，但也 致力于指导演讲、工作申请和谈判策略。这次培训将帮助我 在校外机构获得终身教职 本建议的研究目标是剖析的作用（目标1）和详细的机制（目标2）， 线粒体脂肪酸β-氧化（FAO）在CD4 T细胞分化和功能中的作用，并进一步评估 改变T细胞中FAO水平的翻译应用（Aim 3）。T细胞是细胞介导免疫的核心。 T细胞分化和相关功能的失调导致多种免疫相关疾病， 如癌症、感染、自身免疫性疾病和炎性疾病。T细胞亚群的分化是 与代谢重组有关代谢重新布线是一种生物能量适应不同的条件， T细胞分化的标志是FAO，这是降解长链脂肪酸的主要分解代谢过程。我有 最近产生的内皮FAO缺陷的条件性基因敲除小鼠，并且已经证明， FAO是体外和体内内皮细胞命运的关键调节剂。另一种遗传小鼠模型， 也产生了T细胞特异性FAO缺陷。使用这种新颖的模式，结合尖端的 生物化学技术，我试图填补差距，在我们的知识的分子基础粮农组织在调控 T细胞分化和相关功能（目标1和2）。此外，目标3的目标是评估 在T细胞相关疾病模型中改变FAO水平的翻译潜力。这一建议意义深远 重要性，因为通过回答粮农组织如何控制T细胞分化和 功能，它将为开发新的代谢为基础的治疗方法奠定坚实的基础， 广泛的免疫相关疾病。在向独立过渡时，拟议的 研究将用于准备NIH R01资助申请。