Identification of epigenetic targets in alcohol adrenal allostasis

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Project Summary There is strong evidence that the mammalian response to stress is an orchestration of endocrine, neural and behavioral processes that, in the face of chronic alcohol, can become maladaptive and propagate further escalations of alcohol intake. However, the relationship between stress and alcohol is bidirectional. On one hand, stress is an etiological factor in the development of alcohol use disorders while on the other hand, pathological (i.e., allostatic) adaptations in the stress response occur due to continued use. Activation of the stress axis leads to an increase in circulating adrenal steroids, including glucocorticoids (cortisol), mineralocorticoids (deoxycorticosterone and aldosterone) and androgens (dehydroepiandrosterone). These adrenal steroids influence organs and systems throughout the body, including the liver, heart, brain and immune system. Like humans, nonhuman primates (NHPs) show wide individual differences in their chronic intake of alcohol over years and share similar endocrine physiology, particularly within the adrenal gland. Thus, studies that address allostatic mechanisms involving longitudinal adaptations to alcohol self-administration in the stress axis are uniquely possible in NHPs. The studies proposed in this K99/R00 application will test the overall hypothesis that the adrenal cortex undergoes ethanol-induced adaptation, reflected by aberrant steroid secretion and associated with differential DNAm. The hormonal and epigenetic information from this monkey model will be used to create an in vitro model that will validate the direct effects of alcohol on the adrenal cortex and enable future testing of intervention strategies. Given their ability to influence gene expression and ultimately organ function throughout the body, understanding how chronic alcohol and repeated abstinence impact the adrenal steroids is a valuable endeavor. In addition to leading me through the technical aspects of the experiments in this proposal, my mentors are committed to preparing me for a successful transition to an independent faculty position. They will help me hone my written and oral communication skills by providing feedback on manuscripts, grant applications and presentations and provide guidance and support as I develop as my own mentoring and management skills.