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

基本信息

批准号：
8459919
负责人：
Steven M Wolinsky
金额：
$ 85.76万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/8459919
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

项目摘要

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.

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；并非所有接触过该病毒的人都会被感染，而且那些感染该病毒的人会以不同的速度发展为艾滋病。常见的基因变异仅解释了艾滋病毒/艾滋病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影响相对较大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、它们影响的调节网络、它们引入的相关功能改变以及物质使用的影响，我们提出了一种系统生物学方法来识别与病毒生命周期和免疫相关的许多先天免疫反应因素。我们假设具有强烈表型效应的先天免疫或炎症的调节子或效应子的多种尚未鉴定的罕见变体可能对宿主易感性有显着影响。为了解决这一假设，我们聚集了一个具有互补专业领域的多学科团队，采用系统生物学方法来识别具有影响艾滋病毒/艾滋病易感性和药物滥用的独特和重叠功能的基因。将对大规模测量的数据进行网络分析，以破译支撑细胞介导的抵抗力和对艾滋病毒感染的反应的调控网络。多变量相关性分析基因模块对这些扰动的反应，根据它们对表型的加性或协同贡献，将提供对它们的协同相互作用的深入了解，以及一个易于处理、经过验证的数据集，用于识别候选基因，并具有高可信度以供进一步研究。对候选基因的编码区和共有剪接位点进行靶向捕获和大规模并行测序是一种经济高效的策略，可用于识别包含外显子组的感兴趣区间及其剪接变体中的碱基替换、小插入或缺失以及拷贝数变化。根据基于药物暴露和风险概况的表型进行极端数量性状采样，最大限度地提高了测序人数变异发现的能力。对来自 MACS 和 WIHS 的个体进行基因分型变异，所有这些人的特征都是艾滋病毒疾病状况、遗传血统和药物滥用史，提供了一个发现样本量，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变化的功能验证将阐明它们影响艾滋病毒生命周期的机制，并更好地定义复杂的网络及其控制对这些扰动的反应的特性。这种对宿主易感性和药物滥用的假设驱动、系统级分析的结果应该会增加我们对细胞对扰动反应的复杂特性的理解，并提供对艾滋病毒/艾滋病遗传学和发病机制的深入了解。