GR-Mediated Epigenetic Regulation of the CRH Gene

GR 介导的 CRH 基因表观遗传调控

• 批准号: 8517484
• 负责人: Rosalie Marie Uht
• 金额: $ 34.82万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517484
• 关键词: Adrenal Glands; Affect; Animals; Anorexia Nervosa; Arginine; Base of the Brain; Cell Line; Cells; Chromatin; Circadian Rhythms; Corticosterone; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic AMP-Responsive DNA-Binding Protein; Data; Disease; Down-Regulation; Drug Combinations; Drug Targeting; Environment; Enzymes; Epigenetic Process; Family member; Feedback; Fluoxetine; Functional disorder; Gene Expression; Gene Expression Regulation; Generations; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Heterogeneous Nuclear RNA; Histone Acetylation; Histones; Homeostasis; Hormonal; Hour; Hypothalamic structure; Immunohistochemistry; In Vitro; Individual; Kinetics; Label; Lead; Life; Light; Link; Measures; Mediating; Mental Depression; Methylation; Metyrapone; Modeling; Molecular Analysis; Monitor; Nervous system structure; Neuraxis; Neurons; Nuclear Receptors; Pathogenesis; Pattern; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Pituitary Gland; Plasma; Play; Post-Traumatic Stress Disorders; Prozac; Rattus; Regulation; Regulatory Element; Research Design; Role; Schools; Serum; Site; Societies; Steroids; Stress; System; Techniques; Testing; Time; United States; Work; base; biological adaptation to stress; chromatin immunoprecipitation; chromatin modification; design; drug mechanism; experience; genetic regulatory protein; histone modification; hypothalamic pituitary axis; hypothalamic-pituitary-adrenal axis; in vivo; infancy; lifetime risk; novel; nuclear receptor coactivator 1; paraventricular nucleus; parvocellular; promoter; research study; response; stressor; tool; trend

DESCRIPTION (provided by applicant): Nineteen million people a year in the United States experience depression. A potentially lethal disease, depression puts a strain on family members, leads to lost hours at school and work, is costly to treat, and places a substantial burden on society. In light of this, it is surprising that the pathogenesis of depression is still poorly understood. One feature of the illness that is clear - depression is highly correlated with an abnormal response to stress. The stress response is mediated by the hypothalamic-pituitary-adrenal (HPA) axis. Activity of the HPA axis is normally tightly regulated, in large part because the end products, glucocorticoids, are potent down- regulators of the system. In depression, neurons in the hypothalamus that synthesize and secrete the peptide that triggers the stress response, corticotropin-releasing hormone (CRH), are insensitive to glucocorticoid down-regulation. Because these neurons are the final common integrators of inputs from the central nervous system and the hormonal milieu, if they are abnormally responsive, the entire functioning of the axis is negatively affected. The experiments described in this proposal are designed to elucidate mechanisms by which glucocorticoids down-regulate expression of the CRH gene (crh). Aims 1 and 2 take advantage of a relatively new and powerful technique, chromatin immunoprecipitation (ChIP), and a relatively new neuronal cell line (IVB), which has many features of CRH cells in the hypothalamus. Aim 1 is designed to determine which arrays of co-regulatory proteins are required for down-regulation of crh expression. Aim 2 is designed to determine the role that chromatin modification enzymes and their epigenetic marks play in regulating crh. In Aim 3, the work will be taken into an in vivo setting. Data gained from Aims 1 and 2 will guide the in vivo work by narrowing the array of possible candidates to be chosen for analysis. Two in vivo settings will be studied. First, patterns of coregulators and histone modification enzymes will be assessed at the circadian peak and trough of corticosterone (Cort). These experiments will permit analysis of the effect physiological changes in Cort levels exert on coregulators and histone modification enzymes. Second, rats will be administered metyrapone at short time points, and the same parameters assessed as in the circadian studies. Taken together, the studies will permit molecular analysis of epigenetic mechanisms that regulate the stress response. This unique combination of approaches to the study of depression will produce a novel array of data, leading to a greater understanding of mechanisms of HPA regulation, and increasing our ability to identify novel drug targets for the treatment of depression.

描述（由申请人提供）：美国每年有100万人遭受抑郁症。一种潜在的致命疾病，抑郁症会给家庭成员带来压力，导致学校和工作的时间损失，对治疗的代价很高，并且给社会带来了重大负担。鉴于这种情况，令人惊讶的是，抑郁症的发病机理仍然很少了解。疾病的一个特征是明显的 - 抑郁与对压力的异常反应高度相关。应力反应是由下丘脑 - 垂体 - 肾上腺（HPA）轴介导的。 HPA轴的活性通常受到严格的调节，在很大程度上是因为最终产物，糖皮质激素是系统的有效下调节剂。在抑郁症中，下丘脑中的神经元合成并分泌触发压力反应的肽，皮质激素释放激素（CRH）对糖皮质激素下调不敏感。由于这些神经元是中枢神经系统和荷尔蒙环境的最终共同集成剂，如果它们异常响应敏感，则轴的整个功能会对轴的整个功能产生负面影响。该提案中描述的实验旨在阐明糖皮质激素下调CRH基因（CRH）的表达的机制。目标1和2利用了相对较新的功能技术，染色质免疫沉淀（CHIP）和相对较新的神经元细胞系（IVB），该细胞系（IVB）具有下丘脑中CRH细胞的许多特征。 AIM 1旨在确定下调CRH表达需要哪些共同调节蛋白的阵列。 AIM 2旨在确定染色质修饰酶及其表观遗传标记在调节CRH中的作用。在AIM 3中，工作将被带入体内环境。从目标1和2获得的数据将通过缩小选择要分析的可能的候选人来指导体内工作。将研究两个体内设置。首先，将在皮质酮（CORT）的昼夜峰和槽中评估组蛋白修饰酶的模式。这些实验将允许分析CORT水平对核心调节剂和组蛋白修饰酶的影响生理变化。其次，将在短时间点对大鼠进行Metyrapone施用，并评估与昼夜节律相同的参数。综上所述，研究将允许对调节压力反应的表观遗传机制进行分子分析。这种抑郁症研究方法的独特组合将产生一系列新的数据，从而使人们对HPA调节机制有了更大的了解，并提高了我们鉴定出鉴定抑郁症治疗的新型药物靶标的能力。

项目成果

Dexamethasone induces a putative repressor complex and chromatin modifications in the CRH promoter.

地塞米松诱导 CRH 启动子中的假定阻遏物复合物和染色质修饰。

• DOI: 10.1210/me.2013-1079
• 发表时间: 2013
• 期刊: Molecular endocrinology (Baltimore, Md.)
• 作者: Sharma,Dharmendra;Bhave,Shreyas;Gregg,Elaine;Uht,Rosalie
• 通讯作者: Uht,Rosalie

Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression.

• DOI: 10.1371/journal.pone.0161430
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Stacey W;Bhave S;Uht RM
• 通讯作者: Uht RM

Hypothalamic and amygdalar cell lines differ markedly in mitochondrial rather than nuclear encoded gene expression.

• DOI: 10.1186/1471-2164-14-413
• 发表时间: 2013-06-21
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Dalwadi DA;Uht RM
• 通讯作者: Uht RM

Histone deacetylase 1 (HDAC1) participates in the down-regulation of corticotropin releasing hormone gene (crh) expression.

• DOI: 10.1016/j.physbeh.2011.03.026
• 发表时间: 2011-08-03
• 期刊: PHYSIOLOGY & BEHAVIOR
• 影响因子: 2.9
• 作者: Miller, Lydia;Foradori, Chad D.;Lalmansingh, Avin S.;Sharma, Dharmendra;Handa, Robert J.;Uht, Rosalie M.
• 通讯作者: Uht, Rosalie M.