Chromatin structural changes linking drugs of abuse with HIV reactivation

染色质结构变化将滥用药物与艾滋病毒重新激活联系起来

• 批准号: 8321732
• 负责人: JONATHAN H DENNIS
• 金额: $ 35.73万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321732
• 关键词: AIDS/HIV problem; Adverse effects; Architecture; Behavior; Biological Assay; Biology; Cataloging; Catalogs; Cell Cycle; Chromatin; Chromatin Structure; Chromosomes; Clinical; Complement; Complex; Comprehension; Computational algorithm; Cytology; Data; Development; Dimensions; Disease; Drug Addiction; Drug abuse; Epigenetic Process; Event; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genome; Genomics; Goals; HIV; Health; Histone Acetylation; Histone Deacetylase Inhibitor; Human Genome; Immunity; Knowledge; Laboratories; Life; Link; Maps; Measurement; Measures; Microarray Analysis; Microscopy; Mission; Modeling; Modification; Molecular; Nature; Nuclear; Nucleosomes; Organism; Outcome; Pathway Analysis; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Population; Prevention strategy; Process; Public Health; Regulation; Regulator Genes; Research; Role; Site; Systems Biology; Testing; Transcription Initiation Site; United States National Institutes of Health; Work; base; burden of illness; cost; design; disability; drug of abuse; genome-wide; histone modification; innovation; insight; interdisciplinary approach; molecular pathology; psychostimulant; therapeutic effectiveness

DESCRIPTION (provided by applicant): Drug abuse and addiction add a significant challenging dimension to our comprehension of the progression and treatment of HIV/AIDS. A promising class of HIV treatments (Histone Deacetylase Inhibitors, HDI) and psychostimulant drugs of abuse share a common denominator: both cause changes in chromatin structure through the acetylation of histones. The objective of the proposed research is to identify and analyze the functional chromatin regulatory networks associated with HDI and psychostimulant treatment by means of combined measurements of nucleosome distribution, gene expression, histone modifications, chromatin accessibility and nuclear architecture. The central hypothesis is that HDI and psychostimulants will induce distinct but overlapping patterns of chromatin structural change with specific functions in regulatory networks. The rationale for the proposed research is that a catalogue of chromatin regulatory events will link HDI and psychostimulants with specific genomic targets. Guided by strong preliminary data, the hypothesis will be tested by accomplishing two specific aims : (1) Identify HDI- and psychostimulant-induced chromatin and gene regulatory changes, and (2) Define the role of HDI- and psychostimulant-induced chromatin structural changes in complex genetic and epigenetic regulatory networks. The innovative collective use of microarray technology and cytological assays combined with an integrative systems biology analysis will allow the development new models describing the relationship between chromatin structure and genome regulation. This work will contribute a comprehensive view of the chromatin structural changes that different HDIs and psychostimulants have from their initial targets to the final nuclear readout of transcription. Thi contribution is significant because it will reveal specific sites of chromatin regulation for ten different HDIs and for four psychostimulants, providing the first comprehensive insights into the general and locus-specific mechanisms of these compounds in the context of HIV/AIDS. This work will also provide a detailed, comprehensive description of the relationships among fundamental aspects of genome regulation: histone acetylation, nucleosome distribution, chromatin accessibility, three-dimensional nuclear architecture, and transcription. This contribution is significant because the characterization of the cascade of nuclear events that elicit the chromatin regulatory changes will mark an important first step in understanding the crosstalk among the fundamental processes of genome regulation. This work will represent a new direction that will yield immediate and widely applicable mechanistic information that will aid in the design of effective strategies for the prevention and treatment of HIV/AIDS in drug abusing populations and further our understanding of fundamental chromatin biology. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because identification and analysis of functional chromatin regulatory networks represents a new direction that will yield fundamental mechanistic information applicable in the design of effective strategies for the prevention and treatment of HIV/AIDS in drug abusing populations. The proposed research is relevant to the NIH mission to seek fundamental knowledge about the nature and behavior of living systems (regulatory genomic organization) and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability (HIV/AIDS and drug abuse).

描述（由申请人提供）：药物滥用和成瘾增加了一个重要的挑战性层面，我们的进展和艾滋病毒/艾滋病的治疗的理解。一类有希望的HIV治疗（组蛋白去乙酰化酶抑制剂，HDI）和滥用的精神兴奋剂药物有一个共同点：两者都通过组蛋白的乙酰化引起染色质结构的变化。拟议的研究的目的是通过核小体分布，基因表达，组蛋白修饰，染色质可及性和核结构的联合测量，识别和分析与HDI和精神兴奋剂治疗相关的功能性染色质调控网络。中心假设是，HDI和精神兴奋剂将诱导不同的，但重叠的模式的染色质结构变化与特定的功能，在监管网络。拟议研究的基本原理是，染色质调节事件的目录将把HDI和精神兴奋剂与特定的基因组靶点联系起来。在强有力的初步数据的指导下，该假设将通过实现两个特定目标进行测试：（1）识别HDI和精神兴奋剂诱导的染色质和基因调控变化，以及（2）定义HDI和精神兴奋剂诱导的染色质结构变化在复杂的遗传和表观遗传调控网络中的作用。微阵列技术和细胞学分析的创新性集体使用与综合系统生物学分析相结合，将允许开发描述染色质结构和基因组调控之间关系的新模型。这项工作将有助于全面了解染色质结构的变化，不同的HDIs和精神兴奋剂，从他们的初始目标，最终核读出转录。这一贡献是重要的，因为它将揭示10种不同的HDIs和4种精神兴奋剂的染色质调节的特定位点，为这些化合物在HIV/AIDS背景下的一般和位点特异性机制提供了第一个全面的见解。这项工作还将提供一个详细的，全面的描述基因组调控的基本方面之间的关系：组蛋白乙酰化，核小体分布，染色质的可及性，三维核结构和转录。这一贡献是显着的，因为引起染色质调控变化的核事件级联的表征将标志着重要的第一步，在理解基因组调控的基本过程之间的串扰。这项工作将代表一个新的方向，将产生直接和广泛适用的机械信息，将有助于 在设计预防和治疗吸毒人群中艾滋病毒/艾滋病的有效策略方面，并进一步加深我们对基本染色质生物学的理解。 公共卫生相关性：拟议的研究与公共卫生相关，因为功能性染色质调节网络的识别和分析代表了一个新方向，将产生适用于设计有效药物的基本机制信息 预防和治疗吸毒人群中艾滋病毒/艾滋病的战略。拟议的研究与NIH的使命有关，即寻求有关生命系统（调控基因组组织）的性质和行为的基本知识，以及这些知识的应用，以增强健康，延长寿命，减少疾病和残疾（艾滋病毒/艾滋病和药物滥用）的负担。