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.
Despite an established role in influencing obesity and related outcomes, the number and functions of distinct tissue macrophage populations in adipose are unknown. This proposal utilizes unbiased transcriptional profiling and experimental immunologic techniques to delineate functional heterogeneity among ATMs, and develop a comprehensive model of ATM biology in mice and humans. Results from this study may aid in the development of personalized approaches to prevent and treat obesity and related sequelae.