Identification of epigenetic targets in alcohol adrenal allostasis

项目摘要 有强有力的证据表明，哺乳动物对压力的反应是内分泌、神经和 面对长期酗酒的行为过程，可能会变得不适应并进一步传播 酒精摄入量的上升。然而，压力和酒精之间的关系是双向的。一方面， 压力是酒精使用障碍发展的一个病因因素，而另一方面，病理因素 由于持续使用，应激反应中会发生(如变态)适应。应力轴导联的激活 增加循环中的肾上腺类固醇，包括糖皮质激素(皮质醇)、盐皮质激素 (脱氧皮质酮和醛固酮)和雄激素(脱氢表雄酮)。这些肾上腺类固醇 影响全身器官和系统，包括肝脏、心脏、大脑和免疫系统。喜欢 人类、非人类灵长类在长期饮酒方面表现出很大的个体差异。 而且有着相似的内分泌生理，尤其是在肾上腺内。因此，研究该地址 在应力轴上涉及酒精自我给药的纵向适应的不平衡机制是 在卫生保健计划中独一无二的可能性。在此K99/R00申请中提出的研究将测试总体 肾上腺皮质经历酒精诱导的适应的假说，反映在异常类固醇上 分泌并与分化的dNaM有关。由此得出的荷尔蒙和表观遗传学信息 猴子模型将被用来创建一个体外模型，该模型将验证酒精对 并使未来的干预策略测试成为可能。考虑到它们影响基因的能力 表达和最终器官功能遍及全身，了解慢性酒精和反复 禁欲对肾上腺类固醇的影响是一项有价值的努力。除了带领我完成技术上的 在这个提议中，我的导师们致力于让我为成功的过渡做好准备 一个独立的教职员工职位。他们将帮助我磨练我的书面和口头沟通技能，通过提供 对手稿的反馈，批准申请和演示，并在我开发过程中提供指导和支持 作为我自己的指导和管理技能。

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.