Autoimmune Hepatitis: Genetic and Environmental Risks

项目总结 自身免疫性肝炎发病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、预测结果和向个体化临床护理模式的过渡。在这份职业生涯中 开发应用，候选人提出了一种假设驱动的研究战略，以解决 AIH在遗传和环境风险领域的重要知识差距。这是建立在最近一次 完成了对AIH患者和由机构KL2奖资助的匹配对照的前瞻性研究。 该研究策略的具体目标是：(1)发展一大批AIH患者和配对患者 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的控制 和新的招募战略；(2)审问与新发病相关的选定环境触发因素 AIH；以及(3)识别新的疾病特异性人类白细胞抗原关联，并评估遗传和环境 互动。为了实现这些目标，候选人将(1)培养一大批患有Well的患者 表型AIH和匹配的对照组，他们接受了仔细的环境风险因素和 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 Illumina MiSeq平台识别假定的人类白细胞抗原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整合了由资深学生组成的多学科团队的深入指导 科学家，基因组学、遗传学和分子流行病学以及免疫学方面的高级课程； 通过开展体验式学习提出研究计划，并进行高度支持性的研究 环境。导师团队，其中包括具有临床和医疗专业知识的独立调查人员 肝脏学(查拉萨尼)、免疫学介导的药物超敏反应和人类白细胞抗原的翻译研究 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(GAO)、 将指导候选人的研究和职业发展。一流的机构基础设施 促进初级调查人员和机构对候选人的大量承诺大大加强了这一点 申请。在这个计划结束时，候选人将处于有利地位，成为一名独立的 自身免疫性肝病和肝基因组学的医生兼研究员。

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.!