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（申请人提供）：项目摘要了解将HIV感染，甲基苯丙胺依赖性和随后的5-羟色胺系统的变化联系起来的生物学机制，这些系统与抑郁症，压力和下丘脑 - 垂体 - 肾上腺轴 - 肾上腺轴 - 肾上腺 - 肾上腺轴的破坏相关，这对于设计新的预防性预防和治疗型和甲基化感染率至关重要。虽然编码5-羟色胺系统的关键调节剂的基因中的多态性变化，包括5-羟色胺转运蛋白（5-HTT），单胺氧化酶A（MAOA）和色氨酸羟化酶2（TPH2），已经备有良好的纪录，表观良好的遗传学调节。表观遗传学被定义为在没有DNA序列而没有变化的基因表达的变化中，已知通过对DNA和染色质和非编码RNA的分子修饰来有助于组织类型和发育阶段特异性基因表达。 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最终，艾滋病毒感染，成瘾和死亡率的发病率更高。我们最近证明，TPH2 5'-UTR具有反义启动子，该反义启动子在体外转录非编码RNA（Chen and Miller，2009）。在特定目标1中，我们将验证该转录本的存在，并评估其参与TPH2基因表达的调节。我们还将评估DNA甲基化和CCCTC结合因子（CTCF）参与TPH2基因表达的调节。表观遗传机制参与了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，以及特定细胞因子和甲基苯丙胺的潜在表观遗传调节。在特定的目标3中，我们将通过比较SIV+和SIV-Rhesus Monkeys的后验尸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，以探索SIV感染的恒河猴中的甲基苯丙胺暴露是否加剧了血清素能基因的表观遗传学修饰。我们预计该项目的发现将有助于我们更好地理解潜在的生物学机制，制定新策略来操纵血清素神经传递，从而更好地治疗HIV和甲基苯丙胺相关的神经精神障碍，从而更好地降低HIV和死亡率的传播和HIV+患者的传播，并增强甲基耐药性和HIV的治疗策略。公共卫生相关性：项目叙事理解艾滋病毒，甲基苯丙胺滥用与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设计新的预防和治疗策略至关重要，这些策略具有很高的合并症。该项目将调查5-羟色胺神经传递的表观遗传调节及其与艾滋病毒和甲基苯丙胺滥用的相关性。我们预计，该项目产生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HIV感染和甲基苯丙胺成瘾及其合并症的新策略。