A Systems-level Approach to Studying HIV/AIDS Susceptibility and Substance Abuse

研究艾滋病毒/艾滋病易感性和药物滥用的系统级方法

• 批准号: 8321794
• 负责人: Steven M Wolinsky
• 金额: $ 97.19万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321794
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affect; Alcohol or Other Drugs use; Alcohols; Area; Biological; Biological Markers; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cells; Chronic; Clinical Trials; Cocaine; Code; Cohort Studies; Complex; Computer Analysis; Computer Simulation; Consensus; DNA Resequencing; Data; Data Set; Databases; Development; Disease; Disease Progression; Drug Exposure; Drug abuse; Environment; Environmental Risk Factor; Epidemiologic Studies; Equilibrium; Exposure to; Frequencies; Gender; Gene Frequency; Genes; Genetic; Genetic Status; Genetic Variation; Genotype; HIV; HIV Infections; Heroin; Immune; Immune response; Immunity; Individual; Individual Differences; Infection; Inflammation; Inflammatory Response; Laboratory Study; Lead; Life Cycle Stages; Measurement; Mediating; Metabolic Pathway; Methodology; Minor; Missense Mutation; Molecular; Molecular Profiling; Natural Immunity; Nicotine; Nonsense Mutation; Opioid; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Play; Predictive Value; Predisposition; Probability; Process; Property; Proteins; RNA Splicing; Race; Recording of previous events; Relative Risks; Resistance; Risk; Role; Sample Size; Sampling; Signal Pathway; Signaling Protein; Site; Substance abuse problem; System; Systems Biology; Testing; Validation; Variant; Viral; Virus; Woman; base; cohort; cost effective; defense response; disorder risk; drug of abuse; exome; gene environment interaction; genetic variant; genome wide association study; high throughput technology; holistic approach; insight; interest; loss of function; macrophage; multidisciplinary; programs; protein protein interaction; research study; response; small molecule; trait

DESCRIPTION (provided by applicant): Chronic exposure to drugs of abuse is associated with an increased risk for infection or HIV disease progression. Genetic and environment factors play an important role in influencing host susceptibility; not all people exposed to the virus become infected, and those who do progress to AIDS at different rates. Common genetic variants explain only a small fraction of the heritable risk for HIV/AIDS, and therefore a significant proportion of risk may be due to the summation of the effects of many low frequency variants of assorted different genes that have relatively large effects on risk. To determine specific causal variants, the regulatory networks they impact, the relevant functional alterations they introduce, and the influence of substance use, we propose a systems biology approach to identify the many innate immune response factors that are relevant to the virus life cycle and immunity. We hypothesize that multiple as-yet-unidentified rare variants of regulators or effectors of innate immunity or inflammation with strong phenotypic effects are likely to contribute significantly to host susceptibility. To address this hypothesis, we have brought together a multidisciplinary team with complementary areas of expertise for a systems biology approach to identify genes with distinct and overlapping functions that affect HIV/AIDS susceptibility and drug abuse. Network analysis will be performed on data from large-scale measurements to decipher regulatory networks underpinning cell-mediated resistance and responses to HIV infection. Multivariate correlations that analyze gene modules underlying the response to these perturbations in terms of their additive or cooperative contributions towards the phenotype will provide insight into their synergistic interactions and a tractable, validated dataset for identifying candidate genes with high-confidence for further study. Targeted capture and massively parallel sequencing of the coding regions and consensus splice sites of candidate genes is a cost-effective strategy for the identification of base substitutions, small insertions or deletions, and copy number changes within exome-containing intervals of interest and their splice variants. Extreme quantitative trait sampling according to phenotype based on both drug exposure and risk profiles maximizes power for variant discovery for the number of people sequenced. Genotyping variants across individuals from the MACS and the WIHS, all of who are characterized for their HIV disease status, genetic ancestries, and histories of substance abuse, gives a discovery sample size that could identify the frequency of specific variants that predispose to disease risk. Functional validation of the predicted function-altering changes in innate immune response factors will elucidate the mechanisms by which they affect the life cycle of HIV and better define the complex networks and their properties that govern responses to these perturbations. The results of this hypothesis-driven, systems-level analysis of host susceptibility and drug abuse should increase our understanding of the complex properties that underlie the cellular response to perturbation and provide insight into the genetics and pathogenesis of HIV/AIDS. PUBLIC HEALTH RELEVANCE: Systems biology approaches towards deciphering the regulatory networks underlying the cellular response to HIV infection in people who abuse drugs should identify genetic variants that have a substantial probability of influencing an individual's vulnerability to HIV/AIDS. A fundamental understanding of the molecular mechanisms through which they do so will lead to informative biomarkers, new insights into the predictive value of clinical trials involving gender and racial groups, and new opportunities for the development of small molecule-based therapies.

描述(由申请人提供)：长期接触滥用药物与感染或艾滋病毒疾病进展的风险增加有关。遗传和环境因素在影响宿主易感性方面发挥着重要作用；并不是所有接触病毒的人都会感染，而那些感染病毒的人以不同的速度发展为艾滋病。常见的基因变异只解释了艾滋病毒/艾滋病可遗传风险的一小部分，因此很大一部分风险可能是由于对风险有相对较大影响的各种不同基因的许多低频变异的影响的总和。为了确定特定的因果变异，它们影响的调控网络，它们引入的相关功能变化，以及物质使用的影响，我们提出了一种系统生物学的方法来识别与病毒生命周期和免疫相关的许多先天性免疫反应因子。我们推测，具有强烈表型效应的天然免疫或炎症的调节因子或效应物的多种尚未确定的罕见变体可能对宿主的易感性有重大贡献。为了解决这一假设，我们召集了一个具有互补专业知识领域的多学科团队，采用系统生物学方法来识别具有不同和重叠功能的基因，这些基因影响艾滋病毒/艾滋病易感性和药物滥用。将对来自大规模测量的数据进行网络分析，以破译支持细胞介导的抵抗和对艾滋病毒感染的反应的调控网络。多变量相关性分析了潜在的基因模块对这些扰动的响应，根据它们对表型的相加或合作贡献，将提供对它们协同作用的洞察，并为进一步研究识别高度可信的候选基因提供一个易处理、有效的数据集。靶向捕获和大规模并行测序候选基因的编码区和一致剪接点是一种经济有效的策略，用于识别碱基替换、小插入或缺失以及包含外显子的感兴趣区间及其剪接变体内的拷贝数变化。根据药物暴露和风险概况的表型进行的极端数量性状抽样，最大限度地提高了对测序人数发现变异的能力。来自Mac和WIHS的个体的基因分型变异，都以他们的艾滋病毒疾病状态、遗传祖先和药物滥用史为特征，给出了一个发现样本量，可以确定易患疾病风险的特定变异的频率。对先天免疫反应因子中预测的功能改变的功能验证将阐明它们影响HIV生命周期的机制，并更好地定义管理对这些扰动的反应的复杂网络及其属性。这一假设驱动的、系统水平的宿主易感性和药物滥用分析的结果应该会增加我们对细胞对扰动反应的复杂性质的理解，并为HIV/AIDS的遗传学和发病机制提供洞察力。 公共卫生相关性：系统生物学方法破译吸毒者对艾滋病毒感染的细胞反应背后的调控网络，应该识别极有可能影响个人健康的遗传变异 对艾滋病毒/艾滋病的脆弱性。通过对分子机制的基本了解，将产生信息丰富的生物标记物，对涉及性别和种族群体的临床试验的预测价值有新的见解，并为基于小分子的疗法的开发提供新的机会。