Human Genetic Susceptibility to Tropical Infectious Diseases

人类对热带传染病的遗传易感性

• 批准号: 7770865
• 负责人: John Leake
• 金额: $ 12.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770865
• 关键词: 5 year old; Adaptor Signaling Protein; Adopted; Alleles; Alternative Splicing; Area; Biological Assay; Biotechnology; Case-Control Studies; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Clinical and Translational Science Awards; Code; Collaborations; Communicable Diseases; Copy Number Polymorphism; Country; Data; Data Set; Defect; Detection; Developed Countries; Developing Countries; Development; Diagnostic; Discipline; Disease; Disease Outcome; Disease susceptibility; Enhancers; Epidemic; Epidemiology; Exons; Failure; Frequencies; Functional RNA; Funding; Future; Gene Expression Regulation; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Hemorrhage; Hepatic; Human; Human Genetics; Human Genome; Icterus; Immune; Immune response; Immune system; Immunogenetics; Immunologics; Infection; Inherited; Integration Host Factors; Intelligence; Intensive Care; Interleukin-1 Receptors; International; Introns; Investigation; Kidney; Kidney Failure; Knowledge; Laboratories; Lead; Leptospira interrogans; Leptospirosis; Lipid A; Lipopolysaccharides; Lung; Lymphocyte antigen; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Minority; Modeling; Molecular; Molecular Target; Multiple Organ Failure; Mus; Mutation; Myelogenous; NIH Program Announcements; Neisseria meningitidis; Nonsense Codon; Nucleic Acid Regulatory Sequences; Organism; Outcome; Pathogen detection; Pathogenesis; Pathway interactions; Patients; Pattern; Pattern Recognition; Pediatrics; Performance; Persons; Phenotype; Physicians; Play; Polymerase Chain Reaction; Population; Populations at Risk; Predisposition; Prevention strategy; Preventive; Principal Investigator; Promoter Regions; Proteins; Public Health; Publishing; RNA Splicing; Refractory; Reporting; Research; Research Design; Research Personnel; Research Project Grants; Research Training; Resolution; Rodent Model; Role; Scientific Advances and Accomplishments; Scientist; Screening procedure; Sepsis; Services; Severities; Severity of illness; Shapes; Shock; Signal Transduction; Single Nucleotide Polymorphism; Site; Source; South America; Specimen; Stratification; Study Subject; Susceptibility Gene; System; TLR2 gene; Technology; Terminator Codon; Testing; Therapeutic; Therapeutic Intervention; Toll-Like Receptor Pathway; Toll-like receptors; Training; Transcription Initiation Site; Translational Research; Translations; Tropical Medicine; United States; United States National Institutes of Health; Vaccines; Variant; Whole Blood; Work; antimicrobial; base; career; career development; clinical care; clinical phenotype; density; disease phenotype; experience; falls; genetic epidemiology; genome wide association study; genome-wide; human disease; improved; in vivo; interdisciplinary approach; interest; mRNA Stability; new technology; novel; pathogen; patient oriented research; programs; promoter; research clinical testing; response; sample collection; sensor; skills; toll-like receptor 4; tool

DESCRIPTION (provided by applicant): We propose to investigate specific and whole-genome level human genetic polymorphisms associated with severe leptospirosis infection. Leptospirosis is a disease of major importance throughout tropical and sub-tropical regions. Its polarized (<5% severe/fatal vs. usually non-severe) clinical features make it an ideal model for phenotype-genotype comparisons. While most patients with leptospirosis recover uneventfully, a minority develop hepatic, renal, and hemorrhagic manifestations, and some die despite intensive care and specific antimicrobial therapy. A rodent model of leptospirosis demonstrates that hypofunctional TLR4 predisposes to severe disease, but confirmation of this finding and exploration of genome-wide associations will be important in humans in whom multifactorial genetic susceptibility are most likely. The candidate is a pediatric infectious disease physician and former Centers for Disease Control and Prevention Epidemic Intelligence Service Officer with substantial field expertise in tropical infectious diseases seeking to acquire career skills focused on genetic susceptibility to severe infectious disease outcomes. He will greatly benefit from dual mentorship provided by Dr. Joseph Vinetz, physician-scientist and K24/R01-supported tropical medicine investigator, and Dr. Nicholas Schork, statistical genetics expert and recent co-recipient of an NIH Clinical Translational Science Award at the Scripps Translational Research Unit/former Co-Director of the UCSD Center for Human Genetics and Genomics. The candidate will take advantage of advanced clinical research programs at UCSD including the GCRC, the Genomics Center, and the Genetic Polymorphism Laboratory which function within ongoing NIH-funded training grants and international research projects. We seek a) to compare TLR2 and TLR4 (and adaptor protein) genotypes among severely and mildly infected leptospirosis patients and b) to determine genome-wide associations with leptospirosis outcome using high-density single nucleotide polymorphism microarray and haplotype analysis to characterize genomic variation associated with severe disease. Both of these approaches are promising leads toward further translational research and improved diagnostic, therapeutic, and preventive strategies. RELEVANCE: This project will provide a means to investigate mechanisms of leptospirosis pathogenesis and will serve as a superb research training mechanism based on the hypothesis that severe infectious disease susceptibility is attributable to specific defects in innate immune detection and signaling and also due to currently uncharacterized genomic variation.

描述（由申请人提供）：我们建议研究与严重钩端螺旋体病感染相关的特定全基因组水平人类遗传多态性。钩端螺旋体病是整个热带和亚热带地区的一种重要疾病。其两极分化（<5% 严重/致命与通常非严重）临床特征使其成为表型-基因型比较的理想模型。虽然大多数钩端螺旋体病患者都能顺利康复，但少数患者会出现肝脏、肾脏和出血症状，有些患者尽管接受了重症监护和特定的抗菌治疗，还是死亡。钩端螺旋体病的啮齿动物模型表明，功能低下的 TLR4 易患严重疾病，但这一发现的确认和全基因组关联的探索对于最有可能存在多因素遗传易感性的人类来说非常重要。该候选人是一名儿科传染病医生，也是前疾病控制和预防中心流行病情报服务官员，在热带传染病方面拥有丰富的现场专业知识，寻求获得专注于严重传染病结果的遗传易感性的职业技能。他将大大受益于医生兼 K24/R01 支持的热带医学研究者 Joseph Vinetz 博士和统计遗传学专家、斯克里普斯转化研究中心 NIH 临床转化科学奖近期共同获得者、加州大学圣地亚哥分校人类遗传学和基因组学中心联合主任 Nicholas Schork 博士提供的双重指导。候选人将利用加州大学圣地亚哥分校的先进临床研究项目，包括 GCRC、基因组中心和遗传多态性实验室，这些实验室在 NIH 资助的正在进行的培训资助和国际研究项目中发挥作用。我们寻求a)比较严重和轻度感染的钩端螺旋体病患者中的TLR2和TLR4（和接头蛋白）基因型，b)使用高密度单核苷酸多态性微阵列和单倍型分析来确定与钩端螺旋体病结果的全基因组关联，以表征与严重疾病相关的基因组变异。这两种方法都有望推动进一步的转化研究和改进的诊断、治疗和预防策略。 相关性：该项目将提供一种研究钩端螺旋体病发病机制的方法，并将作为一种极好的研究培训机制，该机制基于以下假设：严重传染病易感性可归因于先天免疫检测和信号传导的特定缺陷以及目前未知的基因组变异。