The epigenetic link between environmental exposure and adult onset depression

环境暴露与成人抑郁症之间的表观遗传联系

• 批准号: 8591078
• 负责人: Christina Rene Tyler
• 金额: $ 2.85万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591078
• 关键词: Acetylation; Adult; Affect; Animal Model; Antidepressive Agents; Applications Grants; Arsenic; Atrophic; Bangladesh; Behavior; Behavioral; Biological; Biological Process; Brain; Carcinogens; Chromatin; Chronic; Cognition; Cognitive deficits; Complex; Confocal Microscopy; DNA Methylation; Development; Discrimination; Disease; Disease remission; Dose; Educational process of instructing; Environment; Environmental Exposure; Epidemiologic Studies; Epigenetic Process; Etiology; Experimental Designs; Exposure to; Fellowship; Gene Expression; Genes; Genetic Predisposition to Disease; Goals; Heavy Metals; Hippocampus (Brain); Histones; Human; Immunohistochemistry; Incidence; Individual; Knowledge; Laboratories; Lead; Learned Helplessness; Learning; Link; Lysine; Major Depressive Disorder; Measures; Mediating; Memory; Mental Depression; Mental Health; Mental disorders; Metals; Methylation; Modeling; Modification; Molecular; Molecular Target; Mus; Neurons; Neurotoxins; Outcome; Patients; Pattern; Perinatal; Pharmacological Treatment; Policies; Population; Predisposition; Prevention; Regulation; Research; Research Personnel; Research Proposals; Research Technics; Research Training; Swimming; Symptoms; Techniques; Testing; Therapeutic; Toxic Environmental Substances; Toxin; Training; Training Programs; Translations; United States; Work; Writing; adult neurogenesis; base; chromatin immunoprecipitation; depressive symptoms; design; disability; drinking; drinking water; epigenome; experience; gene environment interaction; hippocampal atrophy; histone modification; improved; knowledge base; nerve stem cell; neurogenesis; new therapeutic target; novel; pre-doctoral; programs; public health relevance; research study; skills; stem; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The training proposal outlined in this grant application was designed specifically for the applicant, primarily focusing on the acquisition of several cutting edge techniques, research skills, professional development, and improving biomedical knowledge base. The research component of the training program seeks to determine the mechanism by which arsenic exposure during development increases susceptibility to depression in adulthood and the contribution of altered epigenetic regulation of adult neurogenesis to onset of depression. Depression is a leading cause of disability worldwide, affecting more than 350 million people; despite several pharmacological treatments more than 30% of individuals never receive full remission of symptoms. Arsenic, a ubiquitous metal found in drinking water in low doses, has been shown to result in cognitive deficits and depressive-like symptoms in both animal models and in humans. The mechanism by which arsenic induces these effects is unknown. A goal of this research proposal is to increase understanding about the molecular etiology of arsenic-associated depression by elucidating complex gene by environment interactions during development that influence the functionality of hippocampal neurons. The experiments in this proposal are designed to test the hypothesis that arsenic exposure during development interferes with the epigenetic environment of the hippocampus leading to susceptibility to depression in adulthood. Aim 1 will evaluate depressive-like behavior and hippocampal deficits using several behavioral tasks with and without antidepressant treatment in mice exposed to arsenic in the perinatal period. Additional assessments of hippocampal neurogenesis (proliferation and differentiation) will be done using immunohistochemistry, confocal microscopy, and unbiased stereology with and without antidepressant treatment to confirm the link with depression. Aim 2 will evaluate the impact of perinatal arsenic exposure and subsequent antidepressant treatment on the epigenetic programming of neurogenesis-related genes using qRT-PCR on a neurogenesis microarray and chromatin histone modifications on genes identified by the microarray using chromatin immunoprecipitation. The expected outcome of these aims is the identification of novel epigenetic molecular targets for therapeutic treatment of MDD. This proposal will contribute to the applicant's predoctoral training in neuroepigenetics of mental disorders.

描述(由申请者提供)：本资助申请中概述的培训方案是专门为申请者设计的，主要侧重于获得几项尖端技术、研究技能、专业发展和完善生物医学知识库。培训计划的研究部分试图确定发育过程中砷暴露增加成年后抑郁易感性的机制，以及成人神经发生的表观遗传调节改变对抑郁症发病的贡献。抑郁症是全球残疾的主要原因，影响着3.5亿多人；尽管进行了几种药物治疗，但超过30%的人从未得到症状的完全缓解。砷是一种在低剂量饮用水中普遍存在的金属，已被证明在动物模型和人类中都会导致认知障碍和抑郁样症状。砷诱导这些效应的机制尚不清楚。这项研究的目标之一是通过阐明发育过程中影响海马神经元功能的复杂基因与环境的相互作用，增加对砷相关性抑郁症分子病因学的理解。这项建议中的实验旨在测试一种假设，即发育期间的砷暴露会干扰海马体的表观遗传环境，从而导致成年后易患抑郁症。目的1将使用几种行为任务评估围产期砷暴露小鼠的抑郁样行为和海马区缺陷，包括抗抑郁治疗和不治疗。对海马神经发生(增殖和分化)的其他评估将使用免疫组织化学、共聚焦显微镜和无偏见的体视学方法，包括抗抑郁治疗和非抗抑郁治疗，以确认与抑郁的联系。目的2利用神经发生微阵列上的qRT-PCR技术和染色质免疫沉淀技术对基因芯片确定的基因进行染色质组蛋白修饰，评估围产期砷暴露和随后的抗抑郁治疗对神经发生相关基因表观遗传编程的影响。这些目标的预期结果是识别用于MDD治疗的新的表观遗传分子靶点。这项建议将有助于申请者在精神障碍的神经表观遗传学方面的博士前培训。