CCR5 Regulation and Promoter Variants in HIV-1

HIV-1 中的 CCR5 调控和启动子变体

基本信息

批准号：
8143413
负责人：
Sunil K Ahuja
金额：
$ 34.81万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8143413
关键词：
Acquired Immunodeficiency Syndrome Address Adopted Alleles Attention Autoimmune Diseases Basic Science Birds CCR5 gene CD4 Lymphocyte Count Cell Death Cell Separation Cell surface Cells Chromatin Communicable Diseases Complex DNA DNA Methylation DNA Sequence Data Deletion Mutation Development Disease Disease Progression Dose Employee Strikes Epidemiologic Studies Epigenetic Process Equilibrium Event Exons Flow Cytometry Foundations Functional RNA Funding Future Gene Expression Gene Proteins Gene Silencing Genes Genetic Genetic Polymorphism Genetic Variation Genome Genotype HIV HIV-1 Haplotypes Heritability Highly Active Antiretroviral Therapy Histone Acetylation Histones Human Immune Immunologist Individual Individual Differences Infection Integration Host Factors International Introns Knowledge Laboratories Left Length Link Malignant Neoplasms Memory Messenger RNA Methylation Modification Molecular Molecular Conformation Monozygotic Twinning Monozygotic twins Nuclear Matrix Nucleic Acid Regulatory Sequences Pathogenesis Pattern Peripheral Blood Mononuclear Cell Phenotype Predisposition Proteins Publishing Recovery Refractory Regulation Repression Research Research Personnel Resistance Risk Role Signal Transduction Site Solid Structure Surface T memory cell T-Cell Activation T-Lymphocyte Tail Testing Text Time Transcript Translational Research Twin Multiple Birth Uncertainty Vaccination Variant Viral Viral Load result Work antiretroviral therapy base bench to bedside cell type cohort demethylation gene repression high risk histone modification improved innovation insight interest new therapeutic target novel permissiveness programs promoter protein expression public health relevance response stem tool translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): A critical determinant of interindividual differences in HIV-1 susceptibility and disease progression rates to AIDS is CCR5 expression levels. Delineating the mechanisms that modulate intersubject differences in CCR5 expression levels is thus of indisputable importance and significance for understanding HIV-AIDS pathogenesis, development of effective strategies for treatment, epidemiological studies and vaccination trials. During the past decade, studies from several laboratories including ours have underscored the critical role of genetic variation in the CCR5 locus in variable HIV-AIDS susceptibility. In the past funding cycle, our studies have unraveled both genetic and novel epigenetic mechanisms that influence CCR5 expression. For example, our studies reveal that epigenetic mechanisms such as DNA methylation of specific regulatory regions of CCR5 are key correlates of T cell-type specific and inter-individual differences in CCR5 expression. To extend these studies we propose 3 aims. Specific Aim (SA) 1a will test the hypothesis that methylation status of CCR5 promoter 2 and intron 2 is a determinant of inter-individual differences in CCR5 surface expression levels, independent of CCR5 genotype and other relevant parameters known to influence CCR5 expression (e.g. T cell activation/CCL3L dose). SA1b will test the hypothesis that epigenetic reprogramming/modification of CCR5 DNA methylation status results in repression of CCR5 gene and surface expression. SA #2is a bench to bedside proof-of-principle translational aim that will test the hypothesis that CCR5 DNA methylation status is associated with relevant HIV-AIDS endpoints in well characterized cohorts. SA #3 will test the hypothesis that there are inter-subject differences in the permissiveness of regulatory regions of CCR5 to undergo epigenetic modifications after T cell activation. The proposed research is significant because it will provide critical insights into the complex interplay between the epigenetic and genetic factors that determine variability in CCR5 expression levels, a key phenotype that influences HIV-AIDS pathogenesis. These studies have translational (bench to bedside) utility as they may identify epigenetic correlates of CCR5 that may impact on variable HIV-AIDS susceptibility. These epigenetic signatures of CCR5 expression may also have utility for targeting CCR5 expression, i.e., by epigenetic programming of key methylation sites that influence CCR5 expression. PUBLIC HEALTH RELEVANCE: The studies proposed will provide new insights into the regulation of CCR5, a protein that is critical to HIV susceptibility. These studies may result in advancing our knowledge about factors that influence HIV-AIDS susceptibility.

描述（由申请人提供）：HIV-1 易感性和艾滋病疾病进展率的个体差异的一个关键决定因素是 CCR5 表达水平。因此，描述调节 CCR5 表达水平的个体间差异的机制对于理解 HIV-AIDS 发病机制、制定有效的治疗策略、流行病学研究和疫苗接种试验具有无可争议的重要性和意义。在过去的十年中，包括我们在内的多个实验室的研究强调了 CCR5 基因座遗传变异在不同的 HIV-AIDS 易感性中的关键作用。在过去的资助周期中，我们的研究揭示了影响 CCR5 表达的遗传和新的表观遗传机制。例如，我们的研究表明，CCR5 特定调控区域的 DNA 甲基化等表观遗传机制是 CCR5 表达的 T 细胞类型特异性和个体间差异的关键相关性。为了扩展这些研究，我们提出了 3 个目标。具体目标 (SA) 1a 将检验以下假设：CCR5 启动子 2 和内含子 2 的甲基化状态是 CCR5 表面表达水平个体间差异的决定因素，独立于 CCR5 基因型和已知影响 CCR5 表达的其他相关参数（例如 T细胞活化/CCL3L 剂量）。 SA1b 将检验以下假设：CCR5 DNA 甲基化状态的表观遗传重编程/修饰会导致 CCR5 基因和表面表达的抑制。 SA #2 是一个床边原理验证转化目标，将测试以下假设：CCR5 DNA 甲基化状态与特征明确的队列中的相关 HIV-AIDS 终点相关。 SA #3 将测试以下假设：T 细胞激活后，CCR5 调控区域进行表观遗传修饰的允许程度存在个体间差异。拟议的研究意义重大，因为它将提供关于表观遗传和遗传因素之间复杂相互作用的重要见解，这些因素决定了 CCR5 表达水平的变异性，而 CCR5 表达水平是影响 HIV-AIDS 发病机制的关键表型。这些研究具有转化（从实验室到临床）效用，因为它们可以识别 CCR5 的表观遗传相关性，从而影响不同的 HIV-AIDS 易感性。 CCR5 表达的这些表观遗传特征也可用于靶向 CCR5 表达，即通过影响 CCR5 表达的关键甲基化位点的表观遗传编程。公共健康相关性：拟议的研究将为 CCR5 的调节提供新的见解，CCR5 是一种对 HIV 易感性至关重要的蛋白质。这些研究可能会增进我们对影响艾滋病毒/艾滋病易感性因素的认识。