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:8794566
- 负责人:
- 金额:$ 19.11万
- 依托单位:
- 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:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeAddressAffectAlcohol or Other Drugs useAlcoholsAreaBiologicalBiological MarkersCD4 Positive T LymphocytesCandidate Disease GeneCellsChronicClinical TrialsCocaineCodeCohort StudiesComplexComputer AnalysisComputer SimulationConsensusDNA ResequencingDataData SetDatabasesDevelopmentDiseaseDisease ProgressionDrug ExposureDrug abuseEnvironmentEnvironmental Risk FactorEpidemiologic StudiesEquilibriumExposure toFrequenciesGenderGene FrequencyGenesGeneticGenetic StatusGenetic VariationGenotypeHIVHIV InfectionsHeroinImmuneImmune responseImmunityIndividualIndividual DifferencesInfectionInflammationInflammatory ResponseLaboratory StudyLeadLife Cycle StagesMassive Parallel SequencingMeasurementMediatingMetabolic PathwayMethodologyMinorMissense MutationMolecularMolecular ProfilingNatural ImmunityNicotineNonsense MutationOpioidParticipantPathogenesisPathway AnalysisPathway interactionsPatternPersonsPharmaceutical PreparationsPhenotypePlayPredictive ValuePredispositionProbabilityProcessPropertyProteinsRNA SplicingRaceRecording of previous eventsRelative RisksResistanceRiskRoleSample SizeSamplingSignal PathwaySignaling ProteinSiteSubstance abuse problemSystemSystems BiologyTestingValidationVariantViralVirusWomanbasecohortcost effectivedefense responsedisorder riskdrug of abuseexomegene environment interactiongenetic variantgenome wide association studyhigh throughput technologyholistic approachinsightinterestloss of functionmacrophagemultidisciplinaryprogramsprotein protein interactionrare variantresearch studyresponsesmall moleculetrait
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疾病进展风险增加相关。遗传和环境因素在影响宿主易感性方面起着重要作用;并非所有接触病毒的人都会被感染,并且那些以不同的速度发展为艾滋病的人。常见的遗传变异只能解释艾滋病毒/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各种不同基因的许多低频变异对风险有较大影响的影响的总和。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力相关的许多先天免疫应答因子。我们推测,先天免疫或炎症的调节因子或效应因子的多种尚未鉴定的罕见变异体具有强烈的表型效应,可能对宿主易感性有显著影响。为了解决这一假设,我们汇集了一个多学科的团队,具有互补的专业知识领域的系统生物学方法,以确定影响艾滋病毒/艾滋病易感性和药物滥用的不同和重叠的功能的基因。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。多变量相关性分析基因模块的基础上,这些扰动的加性或合作的贡献对表型的反应,将提供深入了解他们的协同作用和一个易于处理的,验证的数据集,以确定候选基因的进一步研究具有高的信心。候选基因的编码区和共有剪接位点的靶向捕获和大规模平行测序是用于鉴定碱基取代、小插入或缺失以及含有外显子组的感兴趣区间及其剪接变体内的拷贝数变化的具有成本效益的策略。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,可以最大限度地提高测序人数的变异发现能力。来自MACS和WIHS的个体的基因分型变异,所有这些人都以他们的HIV疾病状态,遗传祖先和药物滥用史为特征,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。预测的先天免疫应答因子的功能改变变化的功能验证将阐明它们影响HIV生命周期的机制,并更好地定义复杂的网络及其特性,这些网络及其特性控制对这些扰动的反应。这种假设驱动的,系统级的主机易感性和药物滥用分析的结果,应该增加我们的理解的复杂特性的基础上的细胞响应扰动,并提供深入了解艾滋病毒/艾滋病的遗传学和发病机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Steven M Wolinsky其他文献
Steven M Wolinsky的其他文献
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{{ truncateString('Steven M Wolinsky', 18)}}的其他基金
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
10223024 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
10214768 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
9927860 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
9912209 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
10217306 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
Northwestern CORE Clinical Research Site: Trans-omics for HIV/AIDS Research
西北核心临床研究站点:艾滋病毒/艾滋病研究的跨组学
- 批准号:
10371187 - 财政年份:2019
- 资助金额:
$ 19.11万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 19.11万 - 项目类别:
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:
8637965 - 财政年份:2012
- 资助金额:
$ 19.11万 - 项目类别:
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:
8828647 - 财政年份:2012
- 资助金额:
$ 19.11万 - 项目类别:
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