Metabolic regulation of innate lymphoid cell function and airway inflammation

项目摘要 我的目标是成为一个顶尖学术研究的肺部免疫代谢的主要研究者 机构。此K22职业转型奖申请描述了我的培训，职业目标， 专业发展，和一个创新的研究项目，这将使我在理想的位置，推出一个 成功的独立项目。在我毕业期间获得的坚实的科学基础上， 博士后培训，并与我的导师和研究社区在这里的充分专业支持， 威尔康奈尔，我已经确定了新的科学挑战，在这个应用程序中详细说明，我将与 尖端工具和创新方法。哮喘等慢性肺部疾病影响数百万人， 然而，目前的治疗方法可能无效，导致不希望的副作用，并治疗症状 而不是原因。迫切需要了解控制肺的分子机制 炎症，以设计新的治疗策略。最近的研究表明， 组2先天淋巴样细胞（ILC 2）在驱动慢性肺部炎症，包括哮喘;然而， 控制这种促炎功能的机制还不清楚。特别是， 功能受细胞代谢变化的影响还知之甚少。K22的核心焦点 研究计划是了解代谢信号控制的细胞和生化机制 先天免疫细胞介导的肺部炎症。在新的初步研究中，我发现人类和老鼠 肺ILC 2表达一种被称为芳香烃受体（Ahr）的转录因子，这是一种被广泛认可的 已知影响肺部健康的环境、饮食和微生物衍生代谢物的代谢传感器 和疾病引人注目的是，缺乏Ahr的小鼠具有失调的ILC 2反应，导致保护， 过敏原引起的肺部炎症此外，我发现激活或抑制Ahr信号直接 ILC 2代谢的调节方面，提出了Ahr介导的生物能量变化的假设， 编程可能是ILC 2驱动肺部炎症的能力的基础。使用尖端技术， 代谢分析和免疫生物学，在这个建议中，我将剖析ILC 2-Ahr依赖的机制， 通过研究（1）Ahr信号传导如何影响ILC 2发育， 增殖和功能在体外和体内，和（2）Ahr信号如何影响ILC 2生物能量学和ILC 2的功能， 肺部炎症的发展。重要的是，该研究项目将产生丰富的代谢组学和 测序数据集将有助于未来NIH资金申请的假设生成。鉴于我 背景培训，出版记录，授予技能，学员的指导经验，前沿 工具，以及一个非常支持的导师网络，我非常适合充分利用这一点 奖励，以促进我追求创新的科学研究，并在我的有意义的发现 独立程序。

PROJECT SUMMARY My goal is to become a leading investigator in pulmonary immuno-metabolism at a top-tier academic research institution. This K22 Career Transition Award Application describes my training, career goals, plan for professional development, and an innovative research project that will put me in the ideal position to launch a successful independent program. Building off the strong scientific foundation I gained during my graduate and postdoctoral training, and with the full professional support of my mentor and the research communities here at Weill Cornell, I have identified new scientific challenges detailed in this application that I will address with cutting-edge tools and creative approaches. Chronic lung diseases such as asthma affect millions of Americans and yet current treatments can be ineffective, cause undesired side effects, and treat the symptoms rather than the cause. There is an urgent need to understand the molecular mechanisms controlling lung inflammation in order to design novel therapeutic strategies. Recent studies have demonstrated the importance of Group 2 innate lymphoid cells (ILC2s) in driving chronic lung inflammation including asthma; however, the mechanisms controlling this pro-inflammatory function are not well understood. In particular, whether ILC2 function is affected by changes in cellular metabolism is poorly understood. The central focus of this K22 Research Plan is to understand the cellular and biochemical mechanisms by which metabolic signals control innate immune-cell mediated lung inflammation. In new preliminary studies, I found that human and mouse lung ILC2s express a transcription factor called aryl hydrocarbon receptor (Ahr), which is a well-appreciated metabolic sensor of environmental-, diet-, and microbial-derived metabolites known to influence lung health and disease. Strikingly, mice deficient in Ahr had dysregulated ILC2 responses that resulted in protection from allergen-induced lung inflammation. Furthermore, I found that activation or inhibition of Ahr signaling directly regulated aspects of ILC2 metabolism, raising the hypothesis that Ahr-mediated changes to bioenergetic programming may underlie the ability of ILC2s to drive lung inflammation. Using cutting-edge techniques in metabolic profiling and immunobiology, in this proposal I will dissect the ILC2-Ahr-dependent mechanisms regulating lung tissue inflammation by investigating (1) How Ahr signaling affects ILC2 development, proliferation, and function in vitro and in vivo, and (2) how Ahr signaling affects ILC2 bioenergetics and the development of lung inflammation. Critically, this research project will generate rich metabolomic and sequencing data sets that will contribute to hypothesis generation for future NIH funding applications. Given my background training, publication record, grantmanship skills, mentorship experience of trainees, cutting-edge tools, and an extraordinarily supportive mentorship network, I am ideally-suited to take full advantage of this award to facilitate my pursuit of innovative scientific research and make meaningful discoveries in my independent program.