Autoimmune Hepatitis: Genetic and Environmental Risks

项目摘要 自身免疫性肝炎发病机制的主要遗传和环境危险因素 (AIH)没有得到很好的调查。更好地理解AIH中可解释的风险对于阐明 疾病异质性，预测结果，并过渡到个性化的临床护理模式。在这个职业生涯中 开发应用程序，候选人提出假设驱动的研究策略，以解决 在AIH的遗传和环境风险领域存在重要的知识空白。这是建立在一个最近 完成了对AIH患者和匹配对照的前瞻性研究，该研究由机构KL 2奖资助。 研究策略的具体目标是（1）开发一个大型AIH患者队列， 利用传统的生物学方法，对环境风险因素和相关生物样本进行详细评估， 和新的招募策略;（2）询问与新发病相关的选定环境触发因素 AIH;（3）确定新的疾病特异性HLA相关性，并评估遗传和环境因素 交互.为了实现这些目标，候选人将（1）开发一个大型患者队列， 表型AIH和匹配的对照者进行仔细的环境危险因素评估， 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AIH患者和两个对照组;（3）利用 Illumina MiSeq平台用于识别推定的HLA特异性关联并执行基因环境 互动研究 拟议的职业发展计划纳入了一个多学科的高级管理人员小组的深入指导， 科学家，在基因组学，遗传和分子流行病学和免疫学先进的课程; 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 环境导师团队，其中包括独立的研究人员与专业知识，在临床和 肝病学转化研究（Chalasani）、免疫介导的药物超敏反应和HLA 遗传学（菲利普斯），临床病毒学和指导（古普塔）;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， 为初级调查员提供便利和对候选人的实质性机构承诺大大加强了这一点 应用程序.在这个计划结束时，候选人将很好地定位成为一个独立的 自身免疫性肝病和肝基因组学的医生研究员！

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.!