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

• 批准号: 8010474
• 负责人: GREGORY MICHAEL MILLER
• 金额: $ 28.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010474
• 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; Histocompatibility Testing; Histone Deacetylation; Immune; In Vitro; Incidence; Infection; 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; public health relevance; serotonin transporter; spatiotemporal; treatment strategy

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）：项目摘要了解将HIV感染、甲基苯丙胺依赖和随后的与抑郁、压力和下丘脑-垂体-肾上腺轴破坏相关的5-羟色胺系统变化联系起来的生物学机制，对于设计新的预防和治疗HIV感染和甲基苯丙胺成瘾的策略至关重要，这两者具有很高的共病率。虽然编码5-羟色胺系统的关键调节剂（包括5-羟色胺转运体（5-HTT）、单胺氧化酶A（MAOA）和色氨酸羟化酶2（TPH 2））的基因的多态性变异已被充分记录，但对这些基因的表观遗传调控知之甚少。表观遗传学被定义为在没有DNA序列变化的情况下发生的基因表达的变化，已知其通过对DNA和染色质以及非编码RNA的一系列分子修饰来促进组织类型和发育阶段特异性基因表达。基于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，即TPH 2的表观遗传调节（编码大脑5-羟色胺合成中的限速酶）可能特别是一种潜在机制，通过这种机制，HIV感染和METH依赖可以引起5-羟色胺系统的变化，导致HPA轴功能改变，神经免疫失调，抑郁，并发症的临床治疗和最终，艾滋病病毒感染，成瘾和死亡率较高。我们最近已经证明TPH 2 5 '-UTR具有反义启动子，其在体外转录非编码RNA（Chen和米勒，2009）。在具体目标1中，我们将验证该转录本的存在，并评估其参与TPH 2基因表达的调控。我们还将评估DNA甲基化和CCCTC结合因子（CTCF）在TPH 2基因表达调控中的作用。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组织特异性和发育阶段表达的多巴胺能基因，TPH 2，5-HTT和MAOA，以及在这些基因的潜在表观遗传调控特定的细胞因子和甲基苯丙胺的作用。在具体目标3中，我们将通过比较SIV+和SIV-恒河猴死后组织中的多巴胺能基因的DNA甲基化，评估SIV感染和甲基苯丙胺对多巴胺能基因的表观遗传修饰的影响。我们还将进行一项初步研究，以探讨SIV感染恒河猴的甲基苯丙胺暴露是否会加剧多巴胺能基因的表观遗传修饰。我们预计，该项目的研究结果将有助于我们更好地了解潜在的生物学机制，开发新的策略来操纵5-羟色胺神经传递，以便更好地治疗HIV和甲基苯丙胺相关的神经精神障碍，减少HIV的传播和HIV+患者的死亡率，并加强甲基苯丙胺成瘾和HIV共病的治疗策略。公共卫生关系：了解艾滋病毒、甲基苯丙胺滥用和5-羟色胺系统变化之间的联系，对于为艾滋病和甲基苯丙胺成瘾这两种高并发症设计新的预防和治疗策略至关重要。本计画将探讨五羟色胺神经传递的表观遗传调控及其与爱滋病病毒及甲基安非他命滥用的相关性。我们预计，从这个项目产生的研究结果将提供新的见解的5-羟色胺系统的调节，并将导致新的战略，以治疗艾滋病毒感染和甲基苯丙胺成瘾及其合并症。