Identification of epigenetic targets in alcohol adrenal allostasis

酒精肾上腺动态平衡表观遗传靶点的鉴定

• 批准号: 10214954
• 负责人: Vanessa Jimenez
• 金额: $ 13.85万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2021-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214954
• 关键词: Abstinence; Acute; Address; Adrenal Cortex; Adrenal Glands; Alcohol consumption; Alcohols; Aldosterone; Androgens; Applications Grants; Behavior; Behavioral; Biological; Brain; Cells; Chronic; Collaborations; Communities; Corticosterone; Corticotropin; Cytosine; Dehydroepiandrosterone Sulfate; Deoxycorticosterone; Dependence; Development; Dexamethasone; Diurnal Rhythm; Endocrine; Endocrine Physiology; Epigenetic Process; Ethanol; Etiology; Faculty; Feedback; Female; Foundations; Functional disorder; Future; Gene Expression; Genes; Glucocorticoids; Gonadal structure; Heart; Homeostasis; Hormonal; Human; Hydrocortisone; Hypertension; Immune response; Immune system; Impairment; In Vitro; Incubated; Individual; Individual Differences; Intervention; Investigation; Lead; Liver; Long-Term Effects; Macaca mulatta; Manuscripts; Measures; Mentors; Metabolism; Methods; Methylation; Mineralocorticoids; Modeling; Modification; Monkeys; Neuroendocrinology; Nucleic Acid Regulatory Sequences; Organ; Pathologic; Pathway interactions; Pattern; Physiological; Physiology; Pituitary Hormones; Positioning Attribute; Primates; Process; Protocols documentation; Reporting; Rhesus; Rodent; Role; Self Administration; Sleep disturbances; Steroid biosynthesis; Steroids; Stimulus; Stress; Structure; Testing; Tissues; Training; Withdrawal; Zona Reticularis; absorption; alcohol effect; alcohol research; alcohol use disorder; allostasis; biological adaptation to stress; body system; dehydroepiandrosterone; drinking; epigenome; experimental study; hypothalamic-pituitary-adrenal axis; in vitro Model; male; new therapeutic target; nonhuman primate; novel diagnostics; oral communication; psychologic; relating to nervous system; reproductive function; response; skills; sobriety

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.

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 面对慢性酒精，行为过程可能变得不适应并进一步传播 酒精摄入量的增加。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病因因素，而另一方面， (i.e.,适应性的）适应性的应激反应由于持续使用而发生。激活应力轴电极导线 循环肾上腺类固醇增加，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。像 人类，非人类灵长类动物（NHP）显示出广泛的个体差异，在他们的长期摄入酒精超过 年龄和共享相似的内分泌生理，特别是在肾上腺。因此，研究表明， 在应激轴中，涉及对酒精自我给药的纵向适应的非稳态机制是 在NHP中是唯一可能的。K99/R 00申请中建议的研究将测试 肾上腺皮质经历乙醇诱导的适应性的假说，通过异常的类固醇反应 分泌，并与差异DNAm相关。从这一点上的荷尔蒙和表观遗传信息 将使用猴模型来创建体外模型，该体外模型将验证酒精对 肾上腺皮质，使未来的测试干预策略。考虑到它们影响基因的能力 表达和最终器官功能在整个身体，了解如何慢性酒精和重复 禁欲对肾上腺皮质激素的影响是一项有价值的奋进。除了引导我通过技术 在这个提议中，我的导师们致力于为我的成功过渡做好准备。 一个独立的教师职位。他们将帮助我磨练我的书面和口头沟通技巧，提供 对手稿、资助申请和演示文稿的反馈，并在我开发时提供指导和支持。 作为我自己的指导和管理技能。