Fostering patient-oriented research in cardiometabolic disease pathogenesis and prevention

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The overarching goal of this proposal is to facilitate mentored training of junior investigators in the conduct of high-quality patient-oriented research into cardiometabolic disease pathogenesis. The PI is an Associate Professor of Medicine at the University of Washington whose research program to date has focused on the neurobiological basis of obesity and abnormal glucose metabolism. The current proposal broadens the impact of this work to include cardiovascular disease (CVD) outcomes. The candidate has a productive track record of research mentorship of Fellows and junior faculty clinician-investigators, including K awardees, and academic leadership in promoting mentorship at the departmental level. During this award, the PI will mentor a spectrum of trainees from fields including endocrinology and metabolism, cardiology, pediatrics, and maternal-fetal medicine. The PI will take didactic courses and engage in one-on-one coaching with experienced senior investigators to build mentoring skills. The PI's research program is currently focused on translational studies of cellular processes consistent with possible damage to the primary body-weight and glucose-regulating region of the hypothalamus—the arcuate nucleus. Studies in rodent models show that diet-induced weight gain is dependent on an inflammatory cellular response, known as gliosis, within the arcuate nucleus of the hypothalamus. Gliosis progresses with continued dietary exposure, eventually showing signs of neuron loss. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the PI discovered the first evidence of hypothalamic gliosis in obese humans. The investigators have gone on to show that hypothalamic gliosis 1) is independently related to insulin resistance in humans, 2) correlates with increased levels of visceral fat, 3) is present in obese children, 4) is exacerbated in type 2 diabetes mellitus (T2D), and 5) is improved by Roux-en-Y gastric bypass surgery. Our current projects seek to determine the relationship of hypothalamic gliosis to T2D and the development of glucose intolerance as well as whether hypothalamic gliosis is reversed by obesity treatment. The proposed research extends this work to investigate the implications of hypothalamic gliosis for CVD. Aim 1 tests the relation of hypothalamic gliosis to CVD in humans. To do this, the PI and trainees will conduct an ancillary study to the Framingham Heart Study (FHS). Aim 2 uses an epidemiologic approach to examine dietary risk factors for hypothalamic gliosis within FHS. Aim 3 seeks pilot and feasibility data relating atherosclerosis via carotid imaging and autonomic dysfunction to hypothalamic gliosis. A Mentoring Aim will advance the group's methodology for assessing dietary exposure. Completion of these Aims could provide novel insights into the potential role of the central nervous system in CVD development and critical scientific rationale for future K- and R- level studies. Moreover, the proposed research provides a breadth and depth of opportunities for promising trainees to gain the experience necessary to perform high-quality patient-oriented research on cardiometabolic disease.