Autoimmune Hepatitis: Genetic and Environmental Risks

自身免疫性肝炎：遗传和环境风险

• 批准号: 9898370
• 负责人: Craig S Lammert
• 金额: $ 18.27万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-29 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898370
• 关键词: Active Learning; Acute; Address; Age; Age of Onset; Alleles; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Award; Biological; Biometry; Breast Feeding; Characteristics; Chromosome 6; Clinic; Clinical Research; Clinical Virology; Coffee; Communicable Diseases; Consumption; Control Groups; Data; Data Analyses; Development Plans; Disease; Drug Hypersensitivity; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Ethnic Origin; Exposure to; Family member; Fibrosis; Funding; Future; Gender; Genetic; Genetic Determinism; Genetic Risk; Genetic Variation; Genetic study; Genomic DNA; Genomics; Genotype; Goals; HLA Antigens; Haplotypes; Hepatocyte; Hepatology; Heterogeneity; Histocompatibility Antigens Class I; Immune; Immunologics; Immunology; Individual; Infection; Infrastructure; Investigation; K-Series Research Career Programs; Knowledge; Link; Liver Dysfunction; Liver diseases; Mediating; Medical; Medical History; Mentors; Mentorship; Modeling; Molecular Epidemiology; Natural History; Newly Diagnosed; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Prospective Studies; Prospective cohort; Race; Recording of previous events; Recurrence; Research; Research Personnel; Resolution; Risk; Risk Factors; Sampling; Senior Scientist; Serologic tests; Structure; Surveys; Testing; Tobacco use; Translational Research; Transplantation; Urinary tract infection; Viral; Virus Diseases; base; career; career development; clinical care; cohort; cost effective; deep sequencing; disease heterogeneity; disease phenotype; epidemiologic data; experience; gene environment interaction; genetic epidemiology; genetic risk factor; genetic variant; genomic epidemiology; human leukocyte antigen testing; liver injury; multidisciplinary; novel; outcome prediction; pleiotropism; programs; prospective; recruit; research and development; risk variant; skills; social media; tool; treatment response

PROJECT SUMMARY The principle genetic and environmental risk factors underlying the pathogenesis of autoimmune hepatitis (AIH) are not well investigated. Better understanding the explainable risks in AIH is essential to elucidate disease heterogeneity, predict outcomes, and transition to a model of individualized clinical care. In this career development application, the candidate is proposing a hypothesis-driven research strategy to address important knowledge gaps in the field of genetic and environmental risks in AIH. This builds on a recently completed prospective study of patients with AIH and matched controls funded by an institutional KL2 award. The specific aims of the research strategy are to (1) develop a large cohort of patients with AIH and matched controls with detailed assessment of environmental risk factors and linked biologic samples utilizing traditional and novel recruitment strategies; (2) interrogate selected environmental triggers associated with new onset AIH; and (3) identify novel disease specific HLA associations and assess for genetic and environmental interactions. To achieve these aims, the candidate will (1) develop a large cohort of patients with well phenotyped AIH and matched controls who undergo carefully assessment of environmental risk factors and provide their genomic DNA; (2) systematically interrogate viral and medication-related environmental triggers of newly diagnosed AIH patients and two control groups; (3) conduct HLA deep sequencing utilizing the Illumina MiSeq platform to identify putative HLA-specific associations and perform gene-environment interaction studies. The proposed career development plan integrates in-depth mentoring from a multidisciplinary team of senior scientists, advanced coursework in genomics, genetic and molecular epidemiology, and immunology; experiential learning through the conduct of the proposed research plan, and a highly supportive research environment. The mentorship team, which includes independent investigators with expertise in clinical and translational research in hepatology (Chalasani), immunologic-mediated drug-hypersensitivity and HLA genetics (Phillips), clinical virology and mentoring (Gupta); epidemiologic data analysis and biostatistics (Gao), will guide the candidate's research and career development. The superb institutional infrastructure for facilitating junior investigators and substantial institutional commitment to the candidate greatly strengthen this application. At the conclusion of this program, the candidate will be well positioned to become an independent physician-investigator in autoimmune liver diseases and hepatogenomics.!

项目概要 自身免疫性肝炎发病机制的主要遗传和环境危险因素 （AIH）没有得到很好的研究。更好地理解 AIH 中可解释的风险对于阐明这一点至关重要 疾病异质性、预测结果以及向个体化临床护理模式的转变。在这个职业生涯中 开发应用程序，候选人提出一个假设驱动的研究策略来解决 AIH 遗传和环境风险领域的重要知识差距。这是建立在最近 完成了由 KL2 机构资助的 AIH 患者和匹配对照的前瞻性研究。 研究策略的具体目标是 (1) 开发一大群 AIH 患者并进行匹配 利用传统方法对环境风险因素和相关生物样本进行详细评估进行控制 以及新颖的招聘策略； (2) 询问与新发病相关的选定环境触发因素 艾滋病毒； (3) 识别新的疾病特异性 HLA 关联并评估遗传和环境 互动。为了实现这些目标，候选人将 (1) 培养一大批病情良好的患者 表型 AIH 和匹配对照经过仔细评估环境风险因素和 提供他们的基因组DNA； (2) 系统地询问病毒和药物相关的环境触发因素 新诊断的 AIH 患者和两个对照组； (3)利用HLA深度测序 Illumina MiSeq 平台可识别假定的 HLA 特异性关联并执行基因-环境分析 相互作用研究。 拟议的职业发展计划整合了多学科高级团队的深入指导 科学家，基因组学、遗传和分子流行病学以及免疫学方面的高级课程； 通过拟议的研究计划进行体验式学习，以及高度支持的研究 环境。指导团队包括具有临床和临床专业知识的独立研究人员 肝病学转化研究 (Chalasani)、免疫介导的药物超敏反应和 HLA 遗传学（Phillips）、临床病毒学和指导（Gupta）；流行病学数据分析和生物统计学（高）， 将指导候选人的研究和职业发展。一流的机构基础设施 为初级研究者提供便利以及对候选人的实质性机构承诺极大地加强了这一点 应用。在该计划结束时，候选人将处于成为独立人士的有利位置 自身免疫性肝病和肝基因组学领域的医师研究员。！