The role of unique adipose tissue macrophage populations in obesity

独特的脂肪组织巨噬细胞群在肥胖中的作用

• 批准号: 9910385
• 负责人: David Andrew Hill
• 金额: $ 15.36万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910385
• 关键词: 129 Mouse; Activities of Daily Living; Adipose tissue; Adoptive Transfer; Advisory Committees; Asthma; Award; Basic Science; Biological Assay; Biology; Bone Marrow; Cardiovascular Diseases; Cells; Childhood; Chimera organism; Clinical; Clinical Immunology; Communities; Complement; Complex; Data; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Environment; Epigenetic Process; Equilibrium; Exhibits; Fellowship; Flow Cytometry; Food Hypersensitivity; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Glucose Intolerance; Goals; Health; Heterogeneity; High Fat Diet; Homeostasis; Human; Hypersensitivity; Immune system; Immunologic Techniques; Immunologist; Immunology; Inbred Strains Mice; Individual; Institution; Insulin; Insulin Resistance; Macrophage Activation; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Mus; Obese Mice; Obesity; Ontology; Organism; Outcome; Pathway interactions; Pattern; Pediatric Hospitals; Pediatrics; Pennsylvania; Phenotype; Philadelphia; Physicians; Physiological; Physiology; Population; Predisposition; Proteins; Protocols documentation; RNA; Research; Research Personnel; Residencies; Resistance; Resources; Role; Scientist; Secure; Series; System; Techniques; Testing; Thinness; Tissues; Training; Training Programs; Translational Research; Universities; Visceral; Vocational Guidance; Weight Gain; Work; base; career; combat; cytokine; data resource; experience; experimental study; human disease; in vivo; lipid metabolism; macrophage; mortality; obesity risk; personalized approach; prevent; response; single cell mRNA sequencing; skills; subcutaneous; training opportunity; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT This proposed five-year training program will develop my independent research career as an academic pediatric allergist/immunologist seeking to better understand how obesity and other metabolic derangements influence atopic disease states such as asthma and food allergy. I have completed an MD and PhD in innate immunology, pediatrics residency training, and am entering my final year of fellowship training in allergy and immunology at the Children’s Hospital of Philadelphia (CHOP). My immediate goal is to refine the essential skills necessary for a successful career as an independent investigator. Specifically, I want to be immersed in the field of metabolism, and gain new expertise with advanced and unbiased transcriptomic techniques to complement my prior training in experimental and clinical immunology. My mentor for this award is Dr. Mitchell Lazar, an eminent physician- scientist and expert in the fields of metabolism and epigenetics. To add depth and breadth to my scientific and career guidance, I am supported by an advisory committee composed of scientists and physician-scientists from relevant and complementary fields. I have secured the complete support of my institution, and will benefit greatly from the unparalleled resources and mentorship available at both CHOP and the University of Pennsylvania over the course of this award. My proposal focuses on how adipose tissue macrophages (ATMs) influence adiposity and obesity-related outcomes. ATMs can protect against or promote obesity depending on context, discordant observations that raise fundamental questions as to the number and functions of distinct ATM populations. Drawing on the expertise of the Lazar lab, I utilized single-cell mRNA sequencing and flow cytometry to identify two, transcriptionally-distinct ATM populations in obese mice and humans. Gene ontology analysis indicated that these ATM subsets are equipped to have distinct functions: one that is proinflammatory and one that is tissue- regulatory. These ATM subsets are differentially regulated in an inbred mouse strain that is genetically-resistant to obesity and an established model of genetic variation in humans, implicating ATM subsets in mediating obesity susceptibility. Together, these findings have led me to develop the hypothesis that ATMs exist in more than one functional state, and that differences in the relative proportion of functionally distinct ATMs influence the adipose tissue environment and susceptibility to obesity. This proposal outlines a series of studies that have the potential to fundamentally reshape our view of ATM biology, and have implications for the development of personalized medical approaches for obesity. Importantly, the skills that I gain through the proposed training program will facilitate my long-term goal of using basic and translational research approaches to understand how obesity and other metabolic derangements influence atopic disease states, such as asthma and food allergy.

项目摘要/摘要 该拟议的五年培训计划将发展我作为学术儿科的独立研究生涯 过敏者/免疫学家寻求更好地了解肥胖和其他代谢发展如何影响 特应性疾病状态，例如哮喘和食物过敏。我已经完成了先天免疫学的医学博士学位和博士学位， 儿科居住培训，并进入了我在过敏和免疫学方面的最后一年培训 费城儿童医院（CHOP）。我的直接目标是完善 作为独立调查员的成功职业。具体来说，我想沉浸在代谢领域， 并通过高级和公正的转录组技术获得新的专业知识，以完成我的先前培训 在实验和临床免疫学中。我获得这个奖项的精神是著名的医生米切尔·拉扎尔（Mitchell Lazar）博士 - 新陈代谢和表观遗传学领域的科学家和专家。为我的科学添加深度和广度 职业指导，我得到了一个由科学家和身体科学家组成的咨询委员会的支持 相关和完整的字段。我已经获得了我机构的完全支持，并将大大受益 从CHOP和宾夕法尼亚大学提供的无与伦比的资源和精神制。 这个奖项的课程。 我的建议重点是脂肪组织巨噬细胞（ATM）如何影响肥胖和与肥胖有关 结果。 ATM可以根据上下文来保护或促进肥胖，不一致的观察 提出有关不同ATM种群的数量和功能的基本问题。画在 Lazar实验室的专业知识，我利用单细胞mRNA测序和流式细胞仪来识别两个， 肥胖小鼠和人类中具有转录赋予的ATM种群。基因本体分析表明 这些ATT子集具有不同的功能：一种是促炎性的，一个是组织 监管。这些ATM子集在遗传性抗性的近交小鼠菌株中受到不同的调节 肥胖和人类遗传变异的既定模型 敏感性。这些发现在一起，使我提出了一个假设，即ATM存在于多个 功能状态，以及功能上不同ATM的相对比例的差异会影响脂肪 组织环境和肥胖症的易感性。该建议概述了一系列具有潜力的研究 从根本上重塑我们对ATM生物学的看法，并对个性化的发展产生影响 肥胖的医学方法。重要的是，我通过拟议的培训计划获得的技能将 促进我使用基本和翻译的研究方法的长期目标，以了解肥胖和 其他代谢发展会影响特应性疾病状态，例如哮喘和食物过敏。