Genetic Epidemiology of Primary Biliary Cirrhosis

描述（由申请人提供）： Konstantinos Lazarzanos的长期研究目标是更好地了解原发性胆汁性肝硬化（PBC）的发病机制，PBC是一种慢性进行性胆汁淤积性肝病，易导致肝衰竭并缩短患者的预期寿命。PBC主要影响女性，在家庭中聚集，抗线粒体抗体（AMA）的存在是诊断的标志。迄今为止，PBC的病因学和病理生理学仍然令人沮丧地难以捉摸，这阻碍了新的合理治疗的发展。通常认为PBC是由遗传易感个体中免疫介导的胆管损伤引起的，作为对可能的环境损伤的反应。然而，尚未阐明PBC易感性和潜在病理生物学中涉及的拟议环境成分和推定遗传基因座。在他提出的研究中，拉扎里恩博士采用遗传流行病学方法来阐明这种神秘疾病的基础机制。在马约诊所培育科学环境和优秀的研究设施和资源，K23指导以患者为导向的研究职业发展奖将提供一个极好的机会，以获得在PBC进行高质量的遗传流行病学研究的重要经验。他提出的研究重点是开发一个详细的研究资源，包括500个基于临床的，表型良好的PBC病例，病例的父母和兄弟姐妹的家庭登记，以及500个与基因组DNA/细胞系和血清生物标本库相关联的匹配良好的基于临床的对照。他的假设是：（i）推定的环境和遗传因素易患PBC;（ii）PBC和AMA表现出家族聚集性。他将利用独特的研究资源：（i）估计与生物学上合理的候选基因，环境暴露（吸烟）和基因/环境相互作用相关的PBC风险;（ii）比较PBC和AMA在病例的父母和兄弟姐妹中的患病率与对照组相比。该奖项将为Lazarlane博士提供受保护的研究时间，以生成和测试有意义的科学数据，获得遗传流行病学和统计遗传分析方面的广泛曝光和专业知识。这项培训和本研究的初步结果将促进他的学术生涯，为他成功竞争独立的同行评审资金做好准备，并制定自己的独立研究计划，致力于胆汁淤积性肝病的学术研究。

DESCRIPTION (provided by applicant): Konstantinos Lazaridis's long-term research objective is to better understand the pathogenesis of Primary Biliary Cirrhosis (PBC) a chronic, progressive cholestatic liver disease that predisposes to hepatic failure and shortens patients' life expectancy. PBC affects mainly women, clusters in families, and the presence of antimitochondrial antibodies (AMA) is the hallmark of diagnosis. To date, the etiology and pathophysiology of PBC remain frustratingly elusive, which, prevents the development of novel rational therapies. It is generally believed that PBC is caused by immune-mediated damage of bile ducts in a genetically predisposed individual as a reaction to probable environmental insult(s). Yet, the proposed environmental constituent(s) and the putative genetic loci involved in PBC susceptibility and the underlying pathobiology have not been elucidated. In his proposed studies, Dr. Lazaridis takes a genetic epidemiology approach to shed light on the underpinning mechanisms of this enigmatic disease. In the nurturing scientific environment and outstanding research facilities and resources of the Mayo Clinic, the K23 Mentored Patient-Oriented Research Career Development Award would provide Dr. Lazaridis with an excellent opportunity to obtain significant experience in conducting high-quality genetic epidemiology studies in PBC. His proposed studies focus on developing a detailed, research resource of 500 clinic-based, well-phenotyped PBC cases, a family registry of the parents and siblings of the cases, and 500 well-matched, clinic-based controls linked to genomic DNA/cell lines and a serum bio-specimens repository. His HYPOTHESES are: (i) putative environmental and genetic factors predispose to PBC; (ii) PBC and AMA exhibit familial aggregation. He will use the unique research resources to: (i) estimate risk of PBC associated with biologically plausible candidate genes, environmental exposure (smoking) and gene/environment interaction; (ii) compare prevalence of PBC and AMA in parents and siblings of cases compared to controls. This award will provide Dr. Lazaridis with protected research time to generate and test, meaningful scientific data, obtain broad exposure and expertise in genetic epidemiology and statistical genetic analysis. This training and the preliminary results of this study will advance his academic career, prepare him to successfully compete for independent peer-reviewed funding, and develop his own independent research program committed to academic research in cholestatic liver diseases.