Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection
高度暴露但对 Mtb 感染具有抵抗力的个体的基因组学和代谢组学特征
基本信息
- 批准号:10208663
- 负责人:
- 金额:$ 77.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:BiologicalBiological AssayCCDC6 geneCause of DeathCellsCessation of lifeCollectionCommunicable DiseasesDataDevelopmentDiagnosisDiseaseEnrollmentEnvironmental Risk FactorExposure toFundingGenesGeneticGenetic PolymorphismGenetic Predisposition to DiseaseGenetic studyGenomicsGoalsHIVHepatitis CHouseholdHumanIncidenceIndiaIndividualInfectionIntegration Host FactorsInterferon Type IIInterventionLeprosyMeasuresMediatingMetabolicMycobacterium tuberculosisOutputPathogenesisPathway interactionsPatientsPhenotypePilot ProjectsPlayPopulationPredispositionPreventionPrevention strategyPublic HealthPulmonary TuberculosisReportingResearchResistanceResolutionRoleSample SizeSouth AfricaStructure of molecular layer of cerebellar cortexTechnologyTest ResultTuberculin TestTuberculosisTuberculosis VaccinesUnited States National Institutes of HealthVaccinesVariantacquired factoradaptive immune responseclinical phenotypecohortexperiencegenetic linkage analysisgenetic predictorsgenetic risk factorgenetic variantgenome wide association studygenomic locusindexinginnovationliquid chromatography mass spectrometrymetabolic profilemetabolomemetabolomicsmultidisciplinarynovel therapeuticsnovel vaccinespreventresistance mechanismresponsesmall moleculetool
项目摘要
Although tuberculosis (TB) has been curable and preventable for nearly 75 years, TB remains a major public
health threat globally, as the world’s leading infectious disease cause of death. Goals to “eliminate” TB by 2035
are unlikely to be achieved in this century with the currently available control strategies. Development of new
therapeutic and prevention tools, such as a TB vaccine, is needed, but such efforts are hampered by
insufficient understanding of the mechanisms of protection against Mycobacterium tuberculosis (Mtb) infection.
Although a host genetic role in protection has long been postulated and family-based linkage studies have had
promising results, no specific genes have yet been carefully characterized. Research efforts to date have been
limited by challenges in defining clinical phenotypes of Mtb resistance, small sample sizes, and difficulty in
measuring the degree of exposure to Mtb. With recent advances in high-throughput micro-array and
sequencing technology, however, large-scale genetic studies are now possible. In the proposed study, we will
enroll a cohort of 4,000 household contacts who have been recently exposed to active TB disease. We will
identify contacts who remain uninfected, despite a well-characterized, high degree of exposure to a TB index
case, and compare them with household contacts who become infected with Mtb. The study will take place in
the high TB incidence settings of India and South Africa. In Aim 1, we will characterize a phenotype for
resistance to Mtb infection using responses to both tuberculin skin test (TST) and interferon-gamma release
assays (IGRA) in a cohort recently exposed to a culture-confirmed active TB index case. By integrating these
TST and IGRA results with rigorous characterization of contacts’ exposure to active TB index cases, we will be
able to identify individuals who have resisted Mtb infection despite a high degree of exposure. In Aim 2, we will
conduct a genome-wide association study (GWAS) to identify common and rare genetic variants associated
with resistance to Mtb infection. We will also investigate the candidate SNPs in previously reported TB-related
genetic loci. In Aim 3, we will leverage the emerging field of metabolomics to identify metabolic profiles that
distinguish individuals resistant to Mtb infection. Identification of metabolic clusters associated with resistance
will reveal cellular pathways involved in resisting or clearing Mtb infection, and will also enhance the GWAS
findings by providing a functional output of the downstream effects of any genetic polymorphisms. This
unbiased and integrated approach will provide an unprecedented opportunity to identify genes and pathways
involved in resistance to Mtb infection, and understand the multi-layered molecular mechanisms underlying TB
infection. Our research team has more than a decade of experience conducting TB, household contact,
genomics and metabolomics studies that will allow us to achieve the innovative scientific aims of this study.
尽管结核病已可治愈和可预防近75年,但结核病仍然是一个主要的公共问题
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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Neel Rajnikant Gandhi其他文献
Neel Rajnikant Gandhi的其他文献
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{{ truncateString('Neel Rajnikant Gandhi', 18)}}的其他基金
Emergence of bedaquiline, pretomanid and linezolid resistance after implementation of new drug-resistant tuberculosis regimens in South Africa
南非实施新的耐药结核病治疗方案后出现贝达喹啉、前托马尼和利奈唑胺耐药性
- 批准号:
10606031 - 财政年份:2022
- 资助金额:
$ 77.52万 - 项目类别:
Emory/Georgia TB Research Advancement Center (TRAC)
埃默里/佐治亚州结核病研究促进中心 (TRAC)
- 批准号:
10429400 - 财政年份:2022
- 资助金额:
$ 77.52万 - 项目类别:
Emory/Georgia TB Research Advancement Center (TRAC)
埃默里/佐治亚州结核病研究促进中心 (TRAC)
- 批准号:
10429399 - 财政年份:2022
- 资助金额:
$ 77.52万 - 项目类别:
Emory/Georgia TB Research Advancement Center (TRAC)
埃默里/佐治亚州结核病研究促进中心 (TRAC)
- 批准号:
10596164 - 财政年份:2022
- 资助金额:
$ 77.52万 - 项目类别:
Emory/Georgia TB Research Advancement Center (TRAC)
埃默里/佐治亚州结核病研究促进中心 (TRAC)
- 批准号:
10596165 - 财政年份:2022
- 资助金额:
$ 77.52万 - 项目类别:
Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection
高度暴露但对 Mtb 感染具有抵抗力的个体的基因组学和代谢组学特征
- 批准号:
10433919 - 财政年份:2018
- 资助金额:
$ 77.52万 - 项目类别:
Mentorship in Patient-Oriented Research in Tuberculosis, HIV and Global Health
结核病、艾滋病毒和全球健康领域以患者为导向的研究指导
- 批准号:
10625368 - 财政年份:2014
- 资助金额:
$ 77.52万 - 项目类别:
Mentorship in Patient-Oriented Research in Tuberculosis, HIV and Global Health
结核病、艾滋病毒和全球健康领域以患者为导向的研究指导
- 批准号:
9898222 - 财政年份:2014
- 资助金额:
$ 77.52万 - 项目类别:
Mentorship and Patient-Oriented Research in Tuberculosis, HIV and Global Health
结核病、艾滋病毒和全球健康领域的指导和以患者为导向的研究
- 批准号:
9064704 - 财政年份:2014
- 资助金额:
$ 77.52万 - 项目类别:
Mentorship and Patient-Oriented Research in Tuberculosis, HIV and Global Health
结核病、艾滋病毒和全球健康领域的指导和以患者为导向的研究
- 批准号:
8790305 - 财政年份:2014
- 资助金额:
$ 77.52万 - 项目类别:
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