Expression and Methylation of HPA Axis Genes in Adult Suicide Brain

成人自杀脑中 HPA 轴基因的表达和甲基化

• 批准号: 9475321
• 负责人: Ghanshyam N Pandey
• 金额: $ 54.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9475321
• 关键词: Adrenal Glands; Adult; Amygdaloid structure; Anterior; Area; Autopsy; Biological Markers; Biological Psychiatry; Brain; Brain region; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; DNA; DNA Methylation; DNA Modification Methylases; DNA Modification Process; DNMT3B gene; DNMT3a; Data; Depressed mood; Depression and Suicide; Development; Diagnosis; Early-life trauma; Enzymes; Epigenetic Process; Feedback; Functional disorder; Gene Abnormality; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Hippocampus (Brain); Hypothalamic structure; Immunoprecipitation; Isoenzymes; Knowledge; Mental Depression; Messenger RNA; Methylation; Mineralocorticoid Receptor; Molecular; Neurobiology; Parahippocampal Gyrus; Patients; Pituitary Gland; Prefrontal Cortex; Proteins; Public Health; Regulation; Research; Risk Factors; Role; Sampling; Schizophrenia; Serotonin; Site; Structure; Substance abuse problem; Suicide; Tacrolimus Binding Proteins; Testing; Therapeutic Agents; Transferase; accomplished suicide; biological adaptation to stress; cingulate cortex; cingulate gyrus; cohort; corticotropin releasing factor-binding protein; epigenetic regulation; glucocorticoid receptor alpha; hypothalamic-pituitary-adrenal axis; interest; mRNA Expression; methylation pattern; novel; promoter; protein expression; public health relevance; pyrosequencing; suicidal behavior; suicide brain; suicide victim

 DESCRIPTION (provided by applicant): Suicide is a major public health concern as about 35,000 people die of suicide in the U.S. every year. Recent studies of patients with suicidal behavior and of postmortem brain samples of suicide victims strongly suggest that suicide is associated with neurobiological abnormalities, such as abnormalities in serotonin function. It has also been observed that suicide and suicidal behavior are associated with abnormal hypothalamic-pituitary- adrenal (HPA) axis function. The molecular mechanisms and causes of HPA axis abnormalities in suicide, however, are not well understood. It is believed that HPA axis abnormalities may be related to an abnormal feedback mechanism and excessive secretion of corticotropin releasing factor (CRF) in the brain. The main objective of our proposal is to examine if HPA axis genes are abnormally expressed in the prefrontal cortex (PFC), anterior cingulate cortex/gyrus (CG), hippocampus, and amygdala of suicide victims. To achieve this specific aim, we will determine the protein and mRNA expression of the HPA axis genes, glucocorticoid receptors (GR-α and GR-β), mineralocorticoid receptors (MR), CRF, the receptors for CRF (CRF-R1 and CRF- R2), CRF binding protein (CRF-BP), and the target genes for GR, which are GILZ and FKBP in the PFC, CG, hippocampus, and amygdala of adult suicide victims of different diagnoses (depression, schizophrenia, other suicide) and in non-suicidal patients with different diagnoses (depression, schizophrenia) as well as normal controls. Abnormalities of epigenetic regulation have been implicated in the regulation of some of the HPA axis genes, especially the GR. We therefore propose to study epigenetic regulation of these genes by examining the effects of DNA methylation on the regulation of HPA axis genes. We propose to determine the protein and mRNA expression of enzymes that methylate DNA (DNA methyl transferase 1 [DNMT1], DNMT3a, and DNMT3b) and hydroxmenthylate DNA (TET1, TET2, and TET3) in the PFC, CG and hippocampus of adult suicide victims, non-suicidal subjects and normal control subjects. We also propose to determine the DNA methylation and hydroxymethylation of promoter proximal regions of HPA axis genes in the PFC, CG and hippocampus of adult suicide victims, non-suicidal patients and controls. We will use methyl DNA immunoprecipitation of DNA (MeDIP) and hydroxymethyl DIP (hMeDIP) to identify differentially ethylated/hydroxymethylated regions of interest in HPA axis genes of adult suicide cohorts. We will validate differences in identified regions using pyrosequencing of DNA isolated from each postmortem region. Together these studies will provide important information to support our hypothesis that suicide is associated with abnormal expression of some of the HPA axis related genes and with abnormal methylation/hydroxymethylation of HPA axis genes critical to the downstream effects of this stress response. These studies will not only enhance our knowledge of the pathophysiology of suicide in general and the role of HPA axis in suicide in particular, but also may result in identifying important sites that may be used for the development of appropriate therapeutic agents for treatment of suicidal behavior and as biomarkers for suicide.

 描述（由适用提供）：自杀是一个主要的公共卫生问题，因为每年约有35,000人死于自杀。最近对自杀行为和自杀后脑样本的患者的最新研究强烈表明，自杀与神经生物学异常有关，例如5-羟色胺功能的异常。还观察到自杀和自杀行为与异常的下丘脑 - 垂体 - 肾上腺（HPA）轴功能有关。但是，自杀中HPA轴异常的分子机制和原因尚不清楚。据认为，HPA轴异常可能与大脑中皮质激素释放因子（CRF）的异常反馈机制和过量分泌有关。我们提案的主要目的是检查HPA轴基因是否在前额叶皮层（PFC），前扣带回皮层/Gyrus（CG），Hampocampus和Amygdala中表达异常。为了实现这一特定目标，我们将确定HPA轴基因，糖皮质激素受体（GR-α和GR-β），盐皮质激素受体（MR），CRF，CRF（CRF-R1和CRF-R2）受体（CRF-R1和CRF-R2），CRF结合蛋白（CRF-BP）的蛋白质和mRNA表达成人自杀诊断（抑郁症，精神分裂症，其他自杀）的海马和杏仁核和非诊断患者（抑郁症，精神分裂症）以及正常对照组的非杀伤性患者。在某些HPA轴基因（尤其是GR）的调节中已经实现了表观遗传调节的异常。因此，我们建议通过检查我们还提出的影响来确定甲基DNA（DNA甲基转移酶1 [DNMT1]，DNMT3A和DNMT3B）的蛋白质和mRNA表达来研究这些基因的表观遗传调节。自杀违规，非杀害受试者和正常对照受试者。我们还建议确定成人自杀受害者，非杀伤性患者和对照组的PFC，CG和海马中HPA轴基因的启动子近端区域的DNA甲基化和羟甲基化。我们将使用DNA（MEDIP）和羟甲基浸入（HMEDIP）的甲基DNA免疫沉淀来鉴定成人自杀同胞HPA轴基因中不同的乙基化/羟基甲基化区域。我们将使用从每个验尸区分离的DNA的焦磷酸测序来验证识别区域的差异。这些研究将共同​​提供重要的信息，以支持我们的假设，即自杀与某些HPA轴相关基因的异常表达以及HPA轴基因的异常甲基化/甲基化/羟基甲基化对这种应激反应的下游效应至关重要。这些研究不仅将增强我们对自杀的病理生理学的了解，尤其是HPA轴的作用，而且还可能导致识别可能用于开发适当治疗剂以治疗自杀行为的重要部位，以治疗自杀行为和作为自杀的生物标志物。