Mario Gil - US grants

PROJECT SUMMARY/ABSTRACT Heart disease is the leading cause of death in the United States and together with cerebrovascular diseases account for over 28% of total deaths in the United States. Acute cardiac events (e.g., myocardial infarction, stress cardiomyopathy, and sudden cardiac death) are concerning because of their unpredictability and the lack of knowledge regarding causative mechanisms. Psychosocial stressors (e.g., anxiety, personality traits, social isolation) overburden the cardiovascular system and are risk factors for cardiovascular events and stroke. Characterization of heart-brain interactions in the context of psychosocial stress is an important first step in identifying gene-environment interactions that are associated with increased disease risk. Researchers have proposed that emotional and psychosocial stress may lead to a sympathetic-catecholaminergic surge that decreases myocyte viability and/or cardiac function. Hypothalamic arginine-vasopressin (AVP) and the V1A receptor (V1AR) have great therapeutic potential for psychosocial stress-associated heart disease, as AVP and its receptors promote health and survival by regulating neuroendocrine stress responses. The main thesis of this proposal is that AVP, acting via the V1AR, promotes health and wellbeing by dynamically modulating neural responses in the ventral tegmental area (VTA) to stressors. AVP is linked to stress-related disorders in humans and altered emotional reactivity in animals, that can be modulated by antipsychotic treatment, suggesting an AVP-VTA interaction in stress-associated responses. However, the neural mechanisms that underlie the relationships among AVP, Avpr1a gene expression, VTA-dependent stress responses, and cardiovascular function have not been fully characterized. To address this gap in knowledge, the major goals of this proposal are to investigate the cardioprotective properties of the neuropeptide AVP and determine whether there is an association between the Avpr1a gene expression, catecholamine release, and heart disease outcomes in a psychosocial stress-induced myocardial injury animal model. Many susceptible individuals are exposed to multiple risk factors that often interact with each other, magnifying cardiovascular disease risk. Using the Syrian hamster, I plan to investigate the interaction between two psychosocial risk factors, social isolation and aggression. Aim 1 will test the hypothesis that AVP in the VTA blocks stress-induced catecholamine release and exacerbation of myocardial ischemia-reperfusion injury, and aim 2 will test the hypothesis that V1AR gene expression patterns will predict response to stress and AVP- treatment on heart injury and catecholamines. The trainee will also participate in career development activities: learn how to perform myocardial ischemia-reperfusion injury surgeries and conduct gene expression studies; participate in a formal career development program; participate in a special program in cardiovascular genetics and epidemiology; complete scientific courses to gain new knowledge; improve grant writing skills by receiving mentorship from experienced investigators; and establish a successful independent research program.