Mechanisms and functions of fatty acid oxidation in T cell differentiation

项目摘要/摘要 通过K22职业发展奖提案，我寻求进一步的指导性研究培训，同时 发展职业技能，以促进向研究独立的成功过渡。因此，这项建议 该计划旨在扩展我在NHLBI Beyond博士后研究期间开发的技能 新陈代谢研究和免疫学。这项建议利用了卓越的科学环境。 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。对这些方法进行培训并协助研究 AIMS，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，一份职业 包括发展计划，以确保通过培养我的口语和能力为学术职位做好充分准备。 书面交流、指导和实验室管理。咨询委员会已组成，成员包括 我的主要导师和其他几位杰出的科学家，他们不仅拥有丰富的科学经验 在与T细胞生物学和细胞代谢相关的领域，这是在这项拨款中提出的，但也有 致力于指导演示文稿、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的职位。 这项建议的研究目标是剖析(目标1)的作用和详细的机制(目标2) 线粒体脂肪酸β氧化(FAO)在CD4T细胞分化和功能中的作用及进一步评价 改变粮农组织T细胞水平的翻译应用(目标3)。T细胞是细胞免疫的中心。 T细胞分化及相关功能的失调导致多种免疫相关疾病， 如癌症、感染、自身免疫性和炎症性疾病。T细胞亚群的分化是 与新陈代谢重新连接有关。代谢重组是一种对不同条件的生物能量适应 T细胞分化的标志是粮农组织，这是一种降解长链脂肪酸的主要分解代谢过程。我有过 最近产生的具有内皮粮农组织缺陷的条件性基因敲除小鼠，并已证明 粮农组织在体外和体内都是内皮细胞命运的关键调节者。另一种遗传性小鼠模型 还产生了T细胞特有的粮农组织缺乏症。使用这一新模式，结合尖端技术 关于生物化学技术，我试图填补我们对粮农组织在监管方面的分子基础的了解空白 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 改变粮农组织水平在T细胞相关疾病模型中的翻译潜力。这项建议意义深远。 重要的是，通过回答粮农组织如何控制T细胞分化和 功能，它将为开发基于代谢的新的治疗方法奠定坚实的基础 广泛的免疫相关疾病。在过渡到独立后，拟议的 研究将被用来准备NIH R01拨款申请。

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.