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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要我的目标是成为顶级学术研究领域肺免疫代谢领域的领先研究者机构。此 K22 职业转型奖申请描述了我的培训、职业目标、计划专业发展和创新研究项目将使我处于理想的位置来启动成功的独立计划。以我在研究生期间获得的坚实科学基础为基础博士后培训，并得到我的导师和研究界的全力专业支持威尔·康奈尔，我在本申请中详细介绍了新的科学挑战，我将解决这些挑战尖端的工具和创造性的方法。哮喘等慢性肺部疾病影响着数百万人美国人目前的治疗方法可能无效，会引起不良副作用，并且只能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。最近的研究表明了重要性第 2 组先天淋巴细胞 (ILC2) 在驱动慢性肺部炎症（包括哮喘）中的作用；然而，控制这种促炎功能的机制尚不清楚。特别是，ILC2 是否功能是否受到细胞代谢变化的影响尚不清楚。 K22的中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，我发现人类和小鼠肺 ILC2 表达一种称为芳基烃受体 (Ahr) 的转录因子，这是一种广受好评的转录因子。已知影响肺部健康的环境、饮食和微生物代谢物的代谢传感器和疾病。引人注目的是，Ahr 缺陷的小鼠 ILC2 反应失调，从而导致对 Ahr 的保护。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 介导的生物能变化的假设编程可能是 ILC2 驱动肺部炎症能力的基础。使用尖端技术代谢分析和免疫生物学，在这个提案中我将剖析 ILC2-Ahr 依赖性机制通过研究 (1) Ahr 信号传导如何影响 ILC2 发育来调节肺组织炎症，增殖、体外和体内功能，以及 (2) Ahr 信号如何影响 ILC2 生物能学和肺部炎症的发展。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 NIH 资助申请生成假设。鉴于我的背景培训、发表记录、资助技能、受训者指导经验、前沿工具和非常支持的指导网络，我非常适合充分利用这一点奖项促进我追求创新科学研究并在我的领域取得有意义的发现独立程序。