Dr. Ari Molofsky is the candidate applying for the K08 Mentored Clinical Scientist Research Career Development Award. Dr. Molofsky is an MSTP graduate and a Hematopathologist, currently serving as a Clinical Instructor at the University of California San Francisco. This career development proposal has two primary goals. First, Dr. Molofsky outlines a 5-year career development plan that includes mentorship by Dr. Richard Locksley, a multidisciplinary committee structured to provide scientific and career advice, didactic coursework, meetings to promote scientific growth and collaborations, as well as workshops on laboratory management and professional skills. Second, Dr. Molofsky outlines a 5-year research strategy to examine fundamental questions related to allergic immunity in adipose tissue. The worldwide prevalence of obesity and type 2 diabetes has risen dramatically, leading to significant morbidity and mortality. Obesity promotes adipose tissue inflammation and is an early event in the development of insulin resistance and progression to frank diabetes. In contrast, a number of immune cells related to allergic, anti-helminth immunity reside in lean adipose tissue and are protective in models of obesity induced insulin resistance and diabetes. Dr. Molofsky's long-term goal is to elucidate the coordinate regulation, cellular interactions, and individual contributions to metabolic homeostasis of allergic immune cells in metabolic health and disease. The objective of this application is to understand the signals that promote the function of adipose tissue lymphocytes, including innate lymphoid type 2 cells (ILC2), adaptive Th2, and regulatory T cells (Treg), as well as the individual contributions to metabolic homeostasis of each cell type in models of obesity and insulin resistance. The central hypothesis of this proposal is that epithelial cytokines, including IL-33, are actively produced in adipose tissue and coordinately regulate ILC2, Th2, and Treg cells, each of which uniquely contribute to metabolic outcomes. Dr. Molofsky will achieve the objective of this proposal by pursuing three specific aims.
In Aim 1, Dr. Molofsky will test the hypothesis that combinations of epithelial cytokines, including IL-33 and TSLP, promote adipose tissue ILC2 function and cytokine secretion. Using unique ILC2 deficient animals, the precise metabolic impact of ILC2 will be assessed.
In Aim 2, Dr. Molofsky will address the regulation and metabolic contributions of adaptive Th2 cells in adipose tissue, testing the hypothesis that Th2 cells provide a mechanism to increase production of allergic immunity-related cytokines with age and after helminth infection.
In Aim 3, Dr. Molofsky will test the hypothesis that the epithelial cytokine IL 33, along with unknown ILC2 factor(s), coordinately regulate and support adipose tissue Tregs, which are protective in models of obesity-induced insulin resistance. This project is relevant to diabetes research and the mission of the NIH and NIDDK because it has the potential to reveal novel cellular and molecular targets related to allergic immunity that are protective against obesity and the development of diabetes.
Obesity is increasing throughout the world and is associated with adipose tissue inflammation, ultimately leading to systemic inflammation, insulin resistance and progression to type 2 diabetes. In contrast, lean adipose tissue supports distinct anti-inflammatory immune cells associated with an allergic immune response. This proposal addresses the regulation and distinct metabolic contributions of adipose tissue allergic immunity- associated lymphocytes, and the data and reagents generated will provide valuable information to inform future therapies targeting obesity and the progression of diabetes.