Obesity is a major public health challenge in the United States and worldwide. The chronic complications and comorbidities from obesity represent one of the greatest challenges to human health. Recent clinical and epidemiological studies have demonstrated the development of asthma to be strongly associated with obesity. In fact, obese asthma patients tend to have increased severity of disease and respond poorly to conventional asthma medications, including corticosteroids. Altogether these observations suggest that obesity-associated asthma may have a distinct molecular pathophysiology compared to other forms of asthma. As such, my long-term research goal is to elucidate the molecular, cellular, and physiological mechanisms that potentiate obesity-associated asthma in order to identify novel therapeutic approaches for the management of this disease. The objective of this proposal is to determine the role of the nuclear hormone receptor PPARg (peroxisome proliferator activated receptor gamma) in TH2 cell effector function and obesity- associated asthma. In previous work, I have discovered that PPARg functions as a brake on TH2 effector function and that the restraint is abolished in the obese state. My central hypothesis is that obesity dysregulates PPARg in TH2 cells to potentiate TH2 cell-driven asthma. I will test this hypothesis using two specific aims.
In Aim 1, I will map the PPARg cistrome in TH2 cells isolated directly from the lungs of lean and obese mice being challenged with experimental asthma to determine if and how the direct and indirect gene targets of PPARg change with changes in metabolic state. I will also map the PPARg cistrome in in vitro differentiated human TH2 cells.
In Aim 2, using lean and obese mice whose T cells are sufficient or deficient in PPARg, I will determine the role of T cell-specific PPARg in the development of obesity-associated asthma. I am an M.D., Ph.D.-trained clinical pathologist working as a UCSF StARR Scholar at the University of California, San Francisco. I am applying for the K38 Award to support my goal of becoming an independent physician scientist. UCSF's exceptional training environment, especially in the fields of immunology, obesity, and asthma, will support my efforts in this regard. Critical elements of my career development plan include mentorship by Dr. Alexander Marson, an expert in utilizing functional genomics approaches to investigate T cell biology in mouse and human; co-mentorship by Dr. Richard Locksley, an expert in Type 2 immunity, helper T cell development, and in vivo immunology; co-mentorship by Dr. John Fahy, an expert in translational asthma research with expertise in obesity-associated asthma; guidance by a multidisciplinary advisory committee which include senior physician-scientists; coursework in data science (R programing), biostatistics, and research ethics; and professional development activities. Taken together, this career development plan will establish a strong foundation on which to build my growing expertise on how obesity alters immune responses.
Obesity is a major and growing public health problem, characterized by several co-morbidities including type 2 diabetes mellitus, cardiovascular disease, renal disease, liver disease, and particular types of cancer. Recent clinical and epidemiological studies have also highlighted obesity as a major risk factor for the development of asthma, which is generally refractory to conventional asthma therapies. We propose to study the molecular pathophysiology of obesity-associated asthma to find ways to better manage this disease.