PEX7 AND IT'S ROLE IN THE PATHOGENESIS OF RCDP

PEX7 及其在 RCDP 发病机制中的作用

• 批准号: 6228936
• 负责人: Nancy Elise Braverman
• 金额: $ 29.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-28 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6228936
• 关键词: X ray; achondroplasia; alleles; cell proliferation; family genetics; gene mutation; genetic models; genetically modified animals; immunocytochemistry; immunofluorescence technique; immunoprecipitation; in situ hybridization; laboratory mouse; northern blottings; pathologic process; peroxisome; phenotype; polymerase chain reaction; protein binding; protein structure function; protein transport; southern blotting; western blottings; yeast two hybrid system

DESCRIPTION (Adapted from investigator's abstract): Rhizomelic chondrodysplasio punctata (RCDP) is a peroxisome biogenesis disorder characterized by cataracts, skeletal abnormalities, profound growth failure and mental retardation. RCDP is inherited as an autosomal recessive trait and is caused by mutations in PEX7, which encodes Pex7p, the receptor for peroxisomal enzymes having a PTS2 sequence. The specific steps involved in the import of PTS2 proteins into peroxisomes are not known, but the P.I. favors a model in which Pex7p binds PTS2 proteins in the cytosol and transports them to the peroxisome. Pex7p contains six WD40 motifs that determine a beta propeller, a structure that provides multiple rigid surfaces for protein interactions. In RCDP, defective function of PTS2 enzymes is thought to produce unknown metabolic alterations that determine the RCDP phenotype. The overall goal of this proposal is to study the molecular and cellular biology of Pex7p and the pathogenesis of RCDP. The P.I. will achieve this by identification and functional analysis of disease related PEX7 mutations in 50+ RCDP probands, and functional analysis of wild type Pex7p. Dr. Braverman will evaluate Pex7p expression, subcellular location and ability to mediate PTS2 protein import. She will also determine the regions of Pex7p that bind PTS2 and interact with other peroxins. These studies will define the steps in PTS2 protein import and allow correlation of PEX7 defects with variations in RCDP phenotypes. The P.I. will generate a murine model of RCDP to investigate the biochemical alterations in PTS2 protein pathways and their relation to tissue pathology. The proposed strategy will utilize cre/lox technologies to engineer hypomorphic, null and conditional PEX7 alleles and produce mice with combinations of these alleles to develop useful models of RCDP. These mice will be characterized by clinical, radiological, histological and biochemical evaluations. This information will contribute to understanding the pathophysiology of RCDP as well as the normal biology of peroxisome assembly and function in bone, lens and CNS development.

描述（改编自调查员的摘要）：根茎软骨增生 Punctata（RCDP）是一种过氧化物酶体生物发生障碍，其特征是白内障， 骨骼异常，严重的生长失败和智力低下。 RCDP是 遗传为常染色体隐性性状，是由PEX7突变引起的 它编码PEX7P，PEX7P是具有PTS2的过氧化物酶体酶的受体 顺序。将PTS2蛋白导入到 过氧化物酶体尚不清楚，但P.I.有利于PEX7P结合的模型 细胞质中的PTS2蛋白并将其转运到过氧化物酶体中。 PEX7P 包含六个确定β螺旋桨的六个WD40主题，该结构是 为蛋白质相互作用提供了多个刚性表面。在RCDP中，有缺陷 人们认为PTS2酶的功能会产生未知的代谢改变 确定RCDP表型。该提议的总体目标是 研究PEX7P的分子和细胞生物学以及RCDP的发病机理。 P.I.将通过疾病的识别和功能分析来实现这一目标 相关的PEX7突变在50+ RCDP概率中以及野生的功能分析 键入PEX7P。 Braverman博士将评估PEX7P表达，亚细胞位置 以及介导PTS2蛋白进口的能力。她还将确定地区 结合PTS2并与其他过氧蛋白相互作用的PEX7P的of。这些研究会 定义PTS2蛋白导入的步骤并允许PEX7缺陷的相关性 RCDP表型的变化。 P.I.将生成一个鼠模型 RCDP研究PTS2蛋白途径和 它们与组织病理学的关系。拟议的策略将利用CRE/LOX 工程师型肌肌，无效和有条件的PEX7等位基因以及 与这些等位基因的组合产生小鼠，以开发有用的模型 RCDP。这些小鼠的特征将以临床，放射学，组织学为特征 和生化评估。这些信息将有助于理解 RCDP的病理生理以及过氧化物酶体的正常生物学 骨骼，镜头和中枢神经系统发育中的组装和功能。