The role of unique adipose tissue macrophage populations in obesity

项目总结/摘要 这项为期五年的培训计划将发展我作为学术儿科的独立研究生涯 过敏症专家/免疫学家寻求更好地了解肥胖和其他代谢紊乱如何影响 特应性疾病状态如哮喘和食物过敏。我完成了先天免疫学的医学博士和博士学位， 儿科住院医师培训，并进入我在过敏和免疫学奖学金培训的最后一年， 费城儿童医院（CHOP）我的近期目标是完善必要的基本技能， 独立调查员的成功职业具体来说，我想沉浸在新陈代谢的领域， 并获得先进和公正的转录组学技术的新专业知识，以补充我之前的培训 在实验和临床免疫学中。我的导师是米切尔·拉扎尔医生，一位杰出的医生- 代谢和表观遗传学领域的科学家和专家。为了增加我的科学和 职业指导，我得到了一个咨询委员会的支持，该委员会由来自 相关和互补的领域。我已经得到了我所在机构的全力支持， 从CHOP和宾夕法尼亚大学提供的无与伦比的资源和指导， 这个奖项的过程。 我的建议集中在脂肪组织巨噬细胞（ATM）如何影响肥胖和肥胖相关的 结果。ATM机可以防止或促进肥胖取决于上下文，不一致的意见， 提出了关于不同ATM种群的数量和功能的基本问题。借鉴 借助Lazar实验室的专业知识，我利用单细胞mRNA测序和流式细胞术鉴定了两种， 在肥胖小鼠和人类中转录不同的ATM群体。基因本体分析表明， 这些ATM亚群具有不同的功能：一个是促炎性的，一个是组织性的， 监管。这些ATM亚群在具有遗传抗性的近交系小鼠品系中受到差异调节 肥胖和人类遗传变异的既定模型，涉及ATM亚群介导肥胖 易感性总之，这些发现使我提出了一个假设，即ATM机存在于不止一个 功能状态，以及功能不同的ATM的相对比例的差异影响脂肪 组织环境和对肥胖的易感性。该提案概述了一系列研究， 从根本上重塑了我们对ATM生物学的看法，并对个性化医疗的发展产生了影响。 肥胖症的治疗方法重要的是，我通过拟议的培训计划获得的技能将 促进我的长期目标，使用基础和转化研究方法来了解肥胖和 其它代谢紊乱影响特应性疾病状态，例如哮喘和食物过敏。

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.