Metabolic regulation of innate lymphoid cell function and airway inflammation

先天淋巴细胞功能和气道炎症的代谢调节

• 批准号: 9647099
• 负责人: Laurel Anne Monticelli
• 金额: $ 16.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-19 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9647099
• 关键词: Activities of Daily Living; Address; Adoptive Cell Transfers; Affect; Age; Agonist; Allergens; American; Aryl Hydrocarbon Receptor; Asthma; Automobile Driving; Award; Biochemical; Bioenergetics; Career Transition Award; Catabolism; Cell Count; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Cessation of life; Child; Chronic; Chronic lung disease; Communities; Data; Data Set; Development; Diet; Disease; Enzymes; Exhibits; Exposure to; Foundations; Funding; Future Generations; Genes; Genetic; Genetic Transcription; Genus Hippocampus; Glucose; Glucose Transporter; Goals; Health; Human; Immune; Immunobiology; In Vitro; Individual; Inflammation; Inflammatory; Institution; Isotope Labeling; Lead; Ligands; Link; Liquid substance; Lung; Lung Inflammation; Lung diseases; Lymphoid Cell; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Nutrient; Oxidative Phosphorylation; Papain; Peptide Hydrolases; Population; Positioning Attribute; Production; Public Health; Publications; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; Research Project Grants; Role; Severities; Severity of illness; Signal Transduction; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Toxic Environmental Substances; Training; United States National Institutes of Health; adaptive immune response; aerobic glycolysis; airway inflammation; aryl hydrocarbon receptor ligand; blood glucose regulation; career; chronic inflammatory disease; comparative; cytokine; design; experience; extracellular; genome-wide; glucose metabolism; glucose uptake; health economics; improved; in vivo; inflammatory lung disease; innovation; lung development; metabolic profile; metabolomics; microbial; mouse model; novel; novel therapeutics; pollutant; post-doctoral training; programs; response; sensor; side effect; skills; symptom treatment; tool; transcription factor; transcriptome; transcriptome sequencing

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.

项目摘要 我的目标是成为顶级学术研究 机构。这个K22职业过渡奖申请描述了我的培训，职业目标，计划 专业发展和一个创新的研究项目，这将使我处于推出的理想位置 成功的独立计划。建立我在毕业生中获得的强大科学基础和 博士后培训，并在我的导师和研究社区的全部专业支持下 威尔·康奈尔（Weill Cornell），我已经确定了本应用程序中详细介绍的新科学挑战 尖端工具和创造性的方法。慢性肺部疾病（例如哮喘）会影响数百万 美国人和目前的治疗可能无效，会引起不希望的副作用，并治疗症状 而不是原因。迫切需要了解控制肺的分子机制 炎症是为了设计新颖的治疗策略。最近的研究表明了重要性 2组先天淋巴样细胞（ILC2）在驱动包括哮喘在内的慢性肺部炎症中；但是， 控制这种促炎功能的机制尚不清楚。特别是ILC2是否 功能受细胞代谢的变化的影响，对此知之甚少。这个K22的主要重点 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，我发现人和老鼠 肺ILC2S表达称为芳基烃受体（AHR）的转录因子，该因子是一种充分欣赏的转录因子 环境，饮食和微生物衍生的代谢产物的代谢传感器已知会影响肺部健康 和疾病。令人惊讶的是，缺乏AHR的小鼠的ILC2反应失调，导致保护免受保护 过敏原诱导的肺部炎症。此外，我发现直接激活或抑制AHR信号传导 ILC2代谢的调节方面，提出了AHR介导的生物能变化的假设 编程可能是ILC2驱动肺部炎症的能力的基础。在 代谢分析和免疫生物学，在此提案中，我将剖析ILC2-AHR依赖机制 通过研究（1）AHR信号如何影响ILC2发育，调节肺组织炎症， 增殖，体外和体内功能，以及（2）AHR信号如何影响ILC2生物能和 肺部炎症的发展。至关重要的是，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为未来的NIH资助应用程序产生假设的生成。给了我 背景培训，出版记录，授予技巧，学员的指导经验，尖端 工具和一个非常支持性的指导网络，我非常适合充分利用这一点 奖励我追求创新的科学研究，并在我的 独立计划。