Chronic inflammation of adipose tissue is now well recognized to be a key factor leading to the development of insulin resistance and eventually type 2 diabetes. However, little is known about the role of different T cell subsets in exacerbating or regulating adipose tissue inflammation induced by obesity. I propose to use mouse genetics to unravel the role of specific T cell subsets in adipose tissue inflammation. Furthermore, I will use mouse genetics and in vitro cultures of T cells to determine how altered regulation of Foxo transcription factors, factor that integrate information concerning the abundance of nutrients, growth factors and stress to regulate a wide range of responses including T cell survival, differentiation and function, affects T cell function in obesity. My lon-term goal is to understand how obesity affects T cells and thus how T cells regulate the development of adipose tissue inflammation, insulin resistance, and type 2 diabetes. In this application I propose to 1) investigate the role of T cell subsets in high fat diet -induced insuli resistance and glucose intolerance, 2) investigate the homing of T regulatory cells to the adipose tissue and, 3) Determine how obesity affects Foxo transcription factors regulation in immune cells and how loss of Foxo transcription factors affects insulin resistance and glucose intolerance. The research proposed in this application will serve as a foundation for my research as an independent investigator. This K01 grant application will be particularly helpful for me to gain independence studying the role of the adaptive immune system in adipose tissue inflammation and insulin resistance, as it will allow me protected time to begin applying my traditional immunology training to the obesity/adipose tissue/insulin resistance research. Additionally, in order to better prepare myself for a career as independent investigator I have developed a career development plan. As part of this application I propose to gain additional training in inflammation research, microarray analysis, microscopy, and cloning;and to attend classes and seminars designed to prepare me for a faculty career including: public speaking, grant writing, chalk talks, and lab management. In my opinion I have already shown my potential to succeed as an independent investigator as I have been productive publishing as a postdoctoral fellow while mentoring other scientists and team teaching a class at San Diego State University as part of the NIH-funded IRACDA program. Finally, it is environment at the University of California San Diego, which has allowed me the opportunities to develop as a researcher, and that I believe will continue to allow me to thrive and grow to eventually become and independent investigator.
It is now well accepted that chronic inflammation induced by obesity is a key factor leading to metabolic syndrome including insulin resistance. However, the role different types of T cells play in this inflammation is at best not completely understood. Using genetics we will probe the specific roles of different T cell types in exacerbating or regulating the chronic inflammation induced by obesity;we will also study the signaling pathways involved in controlling T cells in obesity.
|Allison, Karmel A; Sajti, Eniko; Collier, Jana G et al. (2016) Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells. Elife 5:|
|Stone, Erica L; Pepper, Marion; Katayama, Carol D et al. (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42:239-251|
|Kang, Hannah; Corr, Maripat; Mansson, Robert et al. (2015) Loss of Murine FOXO3 in Cells of the Myeloid Lineage Enhances Myelopoiesis but Protects from K/BxN-Serum Transfer-Induced Arthritis. PLoS One 10:e0126728|
|Mingueneau, Michael; Krishnaswamy, Smita; Spitzer, Matthew H et al. (2014) Single-cell mass cytometry of TCR signaling: amplification of small initial differences results in low ERK activation in NOD mice. Proc Natl Acad Sci U S A 111:16466-71|
|Roupé, Karl Markus; Veerla, Srinivas; Olson, Joshua et al. (2014) Transcription factor binding site analysis identifies FOXO transcription factors as regulators of the cutaneous wound healing process. PLoS One 9:e89274|
|Krishnaswamy, Smita; Spitzer, Matthew H; Mingueneau, Michael et al. (2014) Systems biology. Conditional density-based analysis of T cell signaling in single-cell data. Science 346:1250689|