MOLECULAR ANALYSIS IN ALAGILLE SYNDROME

描述(取自应用程序) Alagille综合征(综合征性胆管缺乏)是一种显性遗传 影响肝脏、心脏、眼睛、脊椎和面部结构的疾病。 表现力是高度可变的，外显性是不完整的，使得 准确的诊断和遗传咨询很困难。人类致病基因 Alagille综合征定位于20号染色体短臂 关于连锁分析和受影响个体的识别 涉及该区域的缺失或易位。这项建议的基础是 候选人在建立试剂方面的初步工作 20号染色体上的阿拉格尔综合征临界区，识别患者 删除或以其他方式重新排列这一关键区域，以及 重新定义临界区的边界。这项建议的目的是 是使用这些试剂来识别在这个区域内映射的基因。 识别表达序列的技术将在 这一建议包括河豚(Fugu)的基因选择和利用 红豆属)共线区，用于鉴定保守序列。 这项提案概述了一项五年培训计划，该计划将使 成为一名独立内科科学家的候选人。该计划 将把授课的努力与密集的动手实验室结合起来 经验。分子与发育相关研究生水平课程 生物课程将在培训的头两年进行， 除了实验室会议和杂志俱乐部。首字母 实验室经验将提供更广泛的接触分子 基因技术不仅适用于完成 这一建议也对随后的分子遗传学研究产生了影响 和发育生物学。该项目利用了 费城儿童医院的多学科小组 确定并开始在临床和分子水平上研究 北美最大的阿拉吉尔患者队列，提供了极好的 有机会研究其临床表达和分子基础 这种紊乱。Alagille综合征致病基因的鉴定 将导致全面的基因型-表型相关性。未来研究 将阐明该基因的功能及其与其他基因的相互作用 分子揭示了一条重要的发育途径，即 它的中断导致了一种具有广泛临床范围的疾病 显化。

DESCRIPTION (taken from application) Alagille syndrome (syndromic bile duct paucity) is a dominant genetic disorder affecting the liver, heart, eye, vertebrae and facial structures. Expressivity is highly variable and penetrance is incomplete, making accurate diagnosis and genetic counseling difficult. The disease gene for Alagille syndrome has been localized to the short arm of chromosome 20 based on linkage analysis and the identification of affected individuals with deletions or translocations involving this region. This proposal builds on the candidate's initial work in establishing reagents from within the Alagille syndrome critical region on chromosome 20, identifying patients with deletions or other rearrangements of this critical region, and redefining the boundaries of the critical region. The aim of this proposal is to use these reagents to identify genes that map within this region. Techniques for identifying expressed sequences that will be focused on in this proposal include cDNA selection and use of the puffer fish (Fugu rubripes) syntenic region to identify conserved sequences. This proposal outlines a five year training program which will allow the candidate to develop into an independent physician scientist. The program will couple didactic efforts with an intensive hands-on laboratory experience. Relevant graduate level courses in molecular and developmental biology will be attended during the first two years of the training period, in addition to laboratory conferences and journal clubs. The initial laboratory experience will provide for a broader exposure to molecular genetic techniques that will be applicable not only to the completion of this proposal but also to subsequent investigations in molecular genetics and developmental biology. This project takes advantage of a multidisciplinary group at The Children's Hospital of Philadelphia, that has identified and begun to study, at the clinical and molecular levels, the largest cohort of Alagille patients in North America, providing an excellent opportunity to study both the clinical expression and molecular basis of this disorder. Identification of the disease gene for Alagille syndrome will lead to a comprehensive genotype-phenotype correlation. Future studies will elucidate the function of this gene and its interactions with other molecules to shed light on an important developmental pathway, the disruption of which results in a disorder with a wide spectrum of clinical manifestation.