Saturday, September 7, 2024
9/7/2024
Project Summary Heart failure is a leading cause of mortality and morbidity in patients with diabetes and obesity, yet much remains unknown regarding the molecular events whereby metabolic disease causes myocardial dysfunction. At the cellular level, oxidative stress and inflammation are considered hallmarks of myocardial impairment. The overarching hypothesis for this F31 fellowship proposal is that the stress response protein regulated in development and DNA damage 1 (REDD1) plays a maladaptive role in the pathogenesis of heart disease by augmenting the development of oxidative stress and inflammation in cardiomyocytes. Preliminary data support that REDD1 expression is enhanced in the heart of mice fed a Western (i.e., high fat, high sucrose) diet and in cardiomyocyte cultures exposed to the saturated fatty acid palmitate. Recent studies from our laboratory demonstrate a key role for REDD1 in the development of diabetes-induced oxidative stress. More specifically, REDD1 acts via a GSK-3β-dependent signaling axis to suppress the nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant response in the retina of diabetic mice. Additionally, REDD1 was found to promote inflammatory signaling in macrophages by direct sequestration of inhibitor of κB (IκB), leading to nuclear factor kappa B (NF-κB) activation. A role for REDD1 in activation of these two non-conventional signaling axes for Nrf2 repression and NF-κB activation has never been interrogated in the heart. Nor is it know if REDD1 contributes to the development of cardiac dysfunction. To test the hypothesis, I will pursue an experimental protocol involving model systems ranging from intact mice to cardiomyocyte cell cultures. Aim 1 will investigate the mechanism whereby consumption of a Western diet promotes transcriptional upregulation of REDD1 in the heart. Aim 2 will investigate the role of REDD1 in the development of oxidative stress and inflammation in cardiomyocytes. Aim 3 will determine the impact of REDD1 deletion on the development of cardiac dysfunction. In addition to my continued graduate training in molecular biology and cellular physiology at Penn State College of Medicine, this fellowship will provide key training opportunities with experts in cardiovascular dysfunction. Specifically, I will learn to properly culture and manipulate adult ventricular cardiomyocytes and develop the technical expertise in echocardiography to assess the impact of REDD1 on cardiac function in transgenic mice. With respect to outcomes, the project will not only expand my skills and systems of analysis beyond those of my primary Sponsor, but will also potentially identify and characterize a unifying regulatory mechanism whereby metabolic disease limits the endogenous antioxidant response and upregulates inflammation in heart. Identification of such a mechanism is significant because it will validate new targets for the development of preventative and/or therapeutic interventions aimed at addressing the molecular basis of heart failure.
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