Metabolic regulation of innate lymphoid cell function and airway inflammation

项目总结 我的目标是在一流的学术研究中成为肺免疫新陈代谢方面的主要研究员。 机构。这份K22职业过渡奖申请表描述了我的培训、职业目标、 职业发展，和一个创新的研究项目，这将使我处于理想的位置，推出一个 成功的独立项目。在我毕业和毕业期间获得的坚实的科学基础上 博士后培训，并在我的导师和这里的研究社区的全力专业支持下 威尔·康奈尔，我已经确定了在这份申请中详细描述的新的科学挑战，我将用 尖端的工具和创造性的方法。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，导致不良副作用，并可治疗症状。 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。最近的研究证明了这一点的重要性 第二组先天淋巴样细胞(ILC2s)在推动包括哮喘在内的慢性肺部炎症中的作用；然而， 控制这种促炎作用的机制还不是很清楚。特别是，ILC2是否 功能受细胞代谢变化的影响目前还知之甚少。这款K22的中心焦点是 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ILC2表达一种被称为芳烃受体(Ahr)的转录因子，这是一种广为人知的 已知影响肺健康的环境、饮食和微生物衍生代谢物的代谢传感器 和疾病。值得注意的是，缺乏AHR的小鼠具有失调的ILC2反应，导致对 过敏原引起的肺部炎症。此外，我发现AHR信号的激活或抑制直接 ILC2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ILC2驱动肺部炎症的能力的基础。使用尖端技术 代谢谱和免疫生物学，在这项建议中，我将剖析ILC2-AhR依赖的机制 通过研究(1)AhR信号如何影响ILC2的发育来调节肺组织炎症， 体外和体内的增殖和功能，以及(2)AhR信号如何影响ILC2生物能量学和 肺部炎症的发展。关键是，这个研究项目将产生丰富的新陈代谢和 对数据集进行排序，这将有助于为未来的NIH资金申请生成假设。鉴于我的 背景培训，出版记录，手腕技能，学员指导经验，前沿 工具，以及一个特别支持的导师网络，我非常适合充分利用这一点 奖项，以促进我追求创新的科学研究，并在我的 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.