Epigenetic Regulation of Serotonin:Relevance to HIV and Methamphetamine Abuse

血清素的表观遗传调控：与艾滋病毒和甲基苯丙胺滥用的相关性

基本信息

批准号：
8233451
负责人：
GREGORY MICHAEL MILLER
金额：
$ 31.98万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233451
关键词：
Acquired Immunodeficiency Syndrome Autopsy Biological Brain CCCTC-binding factor Cell Line Chromatin Clinical Treatment Code Comorbidity DNA DNA Methylation DNA Sequence Development Enzymes Epigenetic Process Functional RNA Gene Expression Gene Expression Regulation Genes Genetic Transcription Grant HIV HIV Infections Health Histocompatibility Testing Histone Deacetylation Immune In Vitro Incidence Infection Interferons Interleukin-6 Lead Link Macaca mulatta Mental Depression Methamphetamine Methamphetamine dependence Modification Monkeys Monoamine Oxidase A Neurons Neurophysiology - biologic function Patients Pilot Projects Primates Regulation Research Role SIV Serotonin Staging Stress System Therapeutic Tissues Transcript Tryptophan 5-monooxygenase Untranslated Regions Variant addiction cytokine demethylation design hypothalamic-pituitary-adrenal axis insight methamphetamine abuse methamphetamine exposure mind control molecular array mortality neuropsychiatry neurotransmission promoter serotonin transporter spatiotemporal treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Project Summary Understanding the biological mechanisms that link HIV infection, methamphetamine dependence and consequent changes in the serotonin system that correlate to depression, stress and disruption of the hypothalamic-pituitary-adrenal axis is critical to designing new preventative and therapeutic strategies for both HIV infection and methamphetamine addiction, which have a high co-morbidity. While polymorphic variations in genes that encode the key modulators of the serotonin system, including the serotonin transporter (5-HTT), monoamine oxidase A (MAOA) and tryptophan hydroxylase 2 (TPH2) have been well-documented, epigenetic regulation of these genes is poorly understood. Epigenetics, which is defined as changes in gene expression that take place without a change in DNA sequence, is known to contribute to tissue-type and developmental stage specific gene expression, via an array of molecular modifications to both DNA and chromatin and non- coding RNAs. Borne out of a line of evidence generated in our lab, this grant explores the hypothesis that epigenetic regulation of TPH2, which codes for the rate limiting enzyme in brain serotonin synthesis, may in particular be an underlying mechanism by which HIV infection and METH dependence can cause changes in the serotonin system that lead to altered HPA axis function, neural-immune dysregulation, depression, complications for clinical treatment and ultimately, higher incidence of HIV infection, addiction and mortality. We have recently demonstrated that TPH2 5'-UTR harbors an antisense promoter, which transcribes a non- coding RNA in vitro (Chen and Miller, 2009). In Specific Aim 1, we will validate the existence of this transcript and assess its involvement in the regulation of TPH2 gene expression. We will also assess the involvement of DNA methylation and CCCTC-binding factor (CTCF) in the regulation of TPH2 gene expression. Epigenetic mechanisms are involved in spatiotemporal expression of numerous genes, as well as in environmental regulation of gene expression. Accordingly, Specific Aim 2 will investigate the role of epigenetic modification in the tissue-specific and developmental stage expression of the serotonergic genes, TPH2, 5-HTT and MAOA, as well as in the potential epigenetic regulation of those genes by specific cytokines and methamphetamine. In Specific Aim 3, we will assess the effect of SIV infection and methamphetamine on the epigenetic modification of the serotonergic genes, by comparing DNA methylation of serotonergic genes in postmortem tissues of SIV+ and SIV- rhesus monkeys. We will also perform a pilot study to explore whether methamphetamine exposure in SIV-infected rhesus monkeys exacerbates epigenetic modification of serotonergic genes. We anticipate that findings of this project will help us to better understand underlying biological mechanisms, develop new strategies to manipulate serotonin neurotransmission so as to treat HIV- and methamphetamine- associated neuropsychiatric disturbances better, reduce the spread of HIV and mortality among HIV+ patients, and enhance treatment strategies for methamphetamine addiction and HIV co-morbidity. PUBLIC HEALTH RELEVANCE: Project Narrative Understanding the link between HIV, methamphetamine abuse and changes in the serotonin system is critical to designing new preventative and therapeutic strategies for both AIDS and methamphetamine addiction, which have high co-morbidity. This project will investigate the epigenetic regulation of serotonin neurotransmission and its relevance to HIV and methamphetamine abuse. We anticipate that the research findings generated from this project will provide new insights into the regulation of the serotonin system and will lead to new strategies to treat HIV-infection and methamphetamine addiction and their co-morbidity.

描述（由申请人提供）：项目摘要了解艾滋病毒感染、甲基苯丙胺依赖以及随后与抑郁、压力和下丘脑-垂体-肾上腺轴破坏相关的血清素系统变化之间的生物学机制对于设计新的预防和治疗方法至关重要。针对艾滋病毒感染和甲基苯丙胺成瘾的治疗策略，这两种疾病具有很高的共病率。虽然编码血清素系统关键调节剂（包括血清素转运蛋白 (5-HTT)、单胺氧化酶 A (MAOA) 和色氨酸羟化酶 2 (TPH2)）的基因的多态性变异已得到充分记录，但这些基因的表观遗传调控尚不清楚。不太了解。表观遗传学被定义为在 DNA 序列不发生变化的情况下发生的基因表达变化，已知通过对 DNA 和染色质以及非编码的一系列分子修饰，有助于组织类型和发育阶段特定的基因表达。 RNA。根据我们实验室产生的一系列证据，这项资助探索了这样一种假设：TPH2（编码大脑血清素合成中的限速酶）的表观遗传调控可能是 HIV 感染和 METH 依赖可能的潜在机制。引起血清素系统的变化，导致 HPA 轴功能改变、神经免疫失调、抑郁、临床治疗并发症，并最终导致 HIV 感染、成瘾和死亡率更高的发生率。我们最近证明 TPH2 5'-UTR 含有反义启动子，可在体外转录非编码 RNA（Chen 和 Miller，2009）。在具体目标 1 中，我们将验证该转录本的存在并评估其在 TPH2 基因表达调节中的参与。我们还将评估 DNA 甲基化和 CCCTC 结合因子 (CTCF) 在 TPH2 基因表达调节中的参与。表观遗传机制涉及许多基因的时空表达以及基因表达的环境调节。因此，具体目标 2 将研究表观遗传修饰在血清素能基因、TPH2、5-HTT 和 MAOA 的组织特异性和发育阶段表达中的作用，以及在特定细胞因子和甲基苯丙胺对这些基因的潜在表观遗传调节中的作用。。在具体目标 3 中，我们将通过比较 SIV+ 和 SIV- 恒河猴死后组织中血清素能基因的 DNA 甲基化来评估 SIV 感染和甲基苯丙胺对血清素能基因表观遗传修饰的影响。我们还将进行一项试点研究，探讨感染 SIV 的恒河猴接触甲基苯丙胺是否会加剧血清素能基因的表观遗传修饰。我们预计该项目的研究结果将帮助我们更好地了解潜在的生物学机制，制定操纵血清素神经传递的新策略，以便更好地治疗艾滋病毒和甲基苯丙胺相关的神经精神障碍，减少艾滋病毒的传播和艾滋病毒+患者的死亡率，以及加强甲基苯丙胺成瘾和艾滋病毒合并症的治疗策略。公共卫生相关性：项目叙述了解艾滋病毒、甲基苯丙胺滥用和血清素系统变化之间的联系对于为艾滋病和甲基苯丙胺成瘾设计新的预防和治疗策略至关重要，这两种疾病的共病率很高。该项目将研究血清素神经传递的表观遗传调控及其与艾滋病毒和甲基苯丙胺滥用的相关性。我们预计该项目的研究结果将为血清素系统的调节提供新的见解，并将导致治疗艾滋病毒感染和甲基苯丙胺成瘾及其共病的新策略。