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：
8828647
负责人：
Steven M Wolinsky
金额：
$ 85.77万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828647
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 Massive Parallel Sequencing 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 rare variant 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）：长期暴露于滥用药物与感染或HIV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起着重要作用。并非所有暴露于病毒的人都被感染，而那些以不同速度发展为艾滋病的人。常见的遗传变异仅解释了艾滋病毒/艾滋病的遗传风险的一小部分，因此，很大一部分的风险可能是由于多种不同基因的许多低频变体的影响总结，这些基因对风险具有相对较大的影响。为了确定特定的因果变异，它们影响的监管网络，他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方法，以识别与病毒生命周期和免疫力相关的许多先天免疫反应因素。我们假设多个尚未确定的调节剂或先天免疫或炎症的效果因子具有强大的表型效应的变体可能对宿主敏感性产生重大贡献。为了解决这一假设，我们将一个具有互补专业知识的多学科团队召集在一起，用于系统生物学方法，以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。网络分析将对从大规模测量到的数据进行对基于细胞介导的抗药性和对HIV感染的反应的数据进行的数据进行。分析对这些扰动响应的基因模块的多元相关性，这些基因对表型的添加剂或合作贡献的响应将提供对其协同相互作用的洞察力，并可以识别出具有高度关注的候选基因的可触及，可验证的，经过验证的数据集，以进行进一步研究。针对候选基因的编码区域和共识剪接位点的有针对性捕获和大规模平行的测序是鉴定基础替代，小插入或缺失的成本效益策略，以及在含量的兴趣间隔内的副本数量变化及其剪接变体。基于药物暴露和风险谱的表型，极端的定量性状采样可最大程度地提高测序人数的变异发现功率。来自MAC和WIH的个体之间的基因分型变异，所有以其HIV疾病状况，遗传祖先和滥用药物的历史的特征，都可以发现发现样本量，可以识别出对疾病风险易患疾病的特定变体的频率。对先天免疫反应因素的预测改变功能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，并更好地定义控制这些扰动响应的复杂网络及其特性。这种假设驱动的，对宿主易感性和药物滥用的系统级分析的结果应增加我们对细胞对扰动反应的复杂特性的理解，并提供对HIV/AIDS的遗传学和发病机理的见解。