Transcriptional Mechanisms Regulating the HIV-1 coreceptor CCR5

调节 HIV-1 辅助受体 CCR5 的转录机制

• 批准号: 8696802
• 负责人: Srinivas Mummidi
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696802
• 关键词: Acquired Immunodeficiency Syndrome; Address; Alleles; Anti-HIV Therapy; Area; Binding; Bioinformatics; Biological Assay; CCL3L1 gene; CCR5 gene; CD4 Lymphocyte Count; Cell Survival; Cells; Cellular Immunity; Chemistry; Code; Collaborations; Communicable Diseases; Complex; DNA-Protein Interaction; Data; Deletion Mutation; Development; Diabetes Mellitus; Disease; Disease Progression; Disease susceptibility; Epigenetic Process; European; Evaluation; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Status; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Graft Rejection; Grant; HIV; HIV-1; Haplotypes; Hepatitis C virus; Heterozygote; Immune response; In Vitro; Individual; Infection; Integration Host Factors; Investigation; Knowledge; Lead; Licensing; Ligands; Link; Maps; Mass Spectrum Analysis; Mediating; Medicine; Molecular; Mutation; Nuclear; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathway interactions; Persons; Phenotype; Population; Positioning Attribute; Predisposition; Proteomics; Regulation; Relative (related person); Role; Single Nucleotide Polymorphism; Site; Stratification; Stream; Surface; System; Systemic disease; T cell differentiation; T-Lymphocyte; Techniques; Testing; Texas; Universities; Vaccines; Variant; Veterans; Viral Load result; authority; base; cell mediated immune response; chromatin immunoprecipitation; design; disease transmission; effective therapy; experience; gain of function; human disease; immunological synapse; improved; in vivo; innovation; insight; interest; knock-down; loss of function; monocyte; novel; novel therapeutics; overexpression analysis; professor; promoter; transcription factor; treatment strategy; vaccine efficacy; vaccine trial

DESCRIPTION (provided by applicant): Interindividual differences in CCR5 expression levels are a critical determinant of HIV-1 susceptibility and progression rate to AIDS. There is strong evidence indicating that these differences could be ascribed to genetic variation in the CCR5 locus. Genetic variability in CCR5 also has been implicated in susceptibility to other infectious and systemic diseases that are relevant to the veteran population. Delineating the mechanisms that modulate intersubject differences in CCR5 expression levels is thus of indisputable importance and significance for understanding pathogenesis of HIV-1 infection and other diseases such as diabetes. There is strong in vitro and in vivo evidence that the polymorphic residues at positions -2135 and -2459 in the CCR5 cis-regulatory region have a dominant effect on its expression. Our studies in this proposal are designed to elucidate the mechanisms by which differential binding of transcription factors to these polymorphisms leads to allele-specific modulation of gene expression resulting in variable CCR5 levels. Specific Aim 1 will test the hypothesis that disease-modifying CCR5 alleles exhibit variable transcription factor binding repertoire. Specific Aim 2 will determine whether the TFs that bind differentially to CCR5 SNPs also influence variable CCR5 expression. We will employ state-of-the art and innovative proteomic and molecular techniques to dissect the complex interactions between the TF binding to CCR5 polymorphisms which lead to variability in CCR5 expression levels. These studies have translational (benchAEbedside) utility as they will identify mechanisms of variable CCR5 expression that may impact on susceptibility to HIV-1/AIDS and other diseases. These molecular studies will capitalize on the vast experience of the PI in transcriptional gene regulation and collaborative efforts with Dr. Jarrett, a leading authority in transcriptional proteomics. There are several down-stream, value-added features of this application: (a) although the studies outlined in this grant will focus on the transcriptional proteomics of CCR5, they are widely applicable to a broad array of genes for which regulatory variation has been implicated in human disease; (b) the results may identify new pathways to target CCR5 expression, thus resulting in development of new therapies; (c) identification of additional genetic determinants that influence CCR5 expression levels. The outlined studies might lead to development of effective treatment strategies and improved vaccination trials and are in line with the goals of VA's Genomic Medicine Initiative.

描述（由申请人提供）： CCR5表达水平的个体差异是HIV-1易感性和对艾滋病的进展率的关键决定因素。有强有力的证据表明，这些差异可以归因于CCR5基因座的遗传变异。 CCR5中的遗传变异性也与对与退伍军人人群相关的其他感染和全身性疾病的敏感性也涉及。因此，描述调节CCR5表达水平中受试者间差异的机制对于理解HIV-1感染和其他疾病（例如糖尿病）的发病机理的重要性和重要性是无可争议的。体外和体内有很强的证据表明，CCR5顺式调节区域中位置的多态性残基-2135和-2459对其表达具有显着作用。我们在该提案中的研究旨在阐明转录因子与这些多态性的差异结合导致基因表达的等位基因特异性调节，从而导致CCR5水平可变的机制。具体目标1将检验以下假设：修改疾病的CCR5等位基因表现出可变的转录因子结合库。特定的目标2将确定与CCR5 SNP差异差异的TF是否也影响可变CCR5表达。我们将采用最新的技术和创新的蛋白质组学和分子技术来剖析TF与CCR5多态性结合之间的复杂相互作用，从而导致CCR5表达水平的可变性。这些研究具有转化（Benchabedside）的实用性，因为它们将确定可变CCR5表达的机制，这些机制可能会影响对HIV-1/艾滋病和其他疾病的易感性。这些分子研究将利用PI在转录基因调节中的巨大经验以及与转录蛋白质组学领先的领先权威Jarrett博士的合作努力。该应用程序有几个下游，增值的特征：（a）尽管该赠款中概述的研究将重点放在CCR5的转录蛋白质组学上，但它们广泛适用于广泛的基因，这些基因已与人类疾病有关的调节性变异与之相关； （b）结果可能会确定靶向CCR5表达的新途径，从而导致新疗法的发展； （c）鉴定影响CCR5表达水平的其他遗传决定因素。概述的研究可能导致开发有效的治疗策略并改善疫苗接种试验，并符合VA基因组医学计划的目标。