This proposal describes a 5-year training program that will expand the applicant's scientific knowledge, advance her expertise in patient-oriented translational research, and establish independence from her primary mentor. A 4-member Mentoring Team and 3-member Advisory Committee will oversee her training and career development. The current application represents a patient-oriented clinical proposal that examines mechanisms of obesity-associated vascular disease in human subjects. Adipose tissue dysfunction, lipotoxicity, and insulin resistance are essential abnormalities linking obesity to the pathogenesis of cardiovascular disease. This proposal will employ a number of complementary approaches harnessing physiological studies of vascular endothelial vasodilator function and angiogenesis, pharmacological and biological methods to probe dysfunctional signaling pathways, and proteomics-based approaches to gain novel insight into the role of a newly identified protein FSP27 in the pathogenesis of vascular disease in obesity.
In aim1, we will investigate the role of FSP27 in depot- specific mechanisms of vascular dysfunction in the human adipose tissue microenvironment, using videomicroscopy and angiogenic assays to examine microvascular responses in both subcutaneous and visceral adipose compartments biopsied during elective surgical procedures, including bariatric surgery, in 150 obese and 50 lean subjects. We will characterize vascular phenotypes in relation to FSP27 signaling and test the hypothesis that down-regulation of FSP27 is linked to insulin resistance and vascular dysfunction.
In aim 2, we will seek to identify molecular mechanisms that contribute to FSP27 regulation of vascular function by employing proteomics-based approaches using mass spectrometry to identify proteins and subsequent pathways differentially modulated by FSP27 in relevance to lipotoxicity, insulin resistance, and vascular biology.
In aim 3, vascular studies, metabolic phenotyping, and proteomics will be repeated at 6-months following bariatric surgical intervention in the same 150 obese subjects from aims 1 and 2. We will test whether relevant FSP27-related molecular pathways identified in aim 2 are influenced by marked weight loss and/or metabolic changes and hypothesize that weight loss will improve vascular phenotype and linked to FSP27 signaling. The overall project will combine molecular biology with human physiology in severely obese individuals where clinically very little vascular data currently exist. The long-term goal of the applicant is to develop an academic career in the field of obesity and cardiovascular disease, and this proposal will allow the applicant to expand her translational expertise in an area that is relatively unexplored and medically important. Obesity will remain one of the most important health care challenges worldwide, and improving our understanding of mechanisms of obesity-related cardiovascular disease is critical.
Obesity has developed into a critical public health problem with the majority of Americans currently categorized as overweight or obese. Cardiovascular disease is the main cause of mortality in this population. This proposal will investigate the novel regulatory role of fat specific protein 27 (FSP27) in mechanisms of vascular disease and insulin resistance which represent areas of high clinical significance in obesity.
