PEX7 AND IT'S ROLE IN THE PATHOGENESIS OF RCDP

描述（改编自研究者摘要）：肢根软骨发育不良 斑点状白内障（RCDP）是一种以白内障为特征的过氧化物酶体生物发生障碍， 骨骼异常，严重的生长障碍和智力迟钝。RCDP是 作为常染色体隐性遗传性状遗传并由PEX 7突变引起， 其编码Pex 7 p，Pex 7 p是具有PTS 2 顺序将PTS 2蛋白导入到细胞中所涉及的具体步骤如下： 过氧化物酶体是未知的，但P.I.支持Pex 7 p结合的模型 PTS 2蛋白在胞质溶胶和运输他们的过氧化物酶体。Pex7p 包含六个WD 40基序，决定了β螺旋桨，一种结构， 为蛋白质相互作用提供了多个刚性表面。在RCDP中，缺陷 PTS 2酶的功能被认为产生未知的代谢改变 决定RCDP表型的基因本提案的总体目标是 研究Pex 7 p的分子生物学和细胞生物学以及RCDP的发病机制。 私家侦探将通过对疾病的识别和功能分析来实现这一目标 50+ RCDP先证者中的相关PEX 7突变，以及野生型的功能分析 Pex 7 p型。Braverman博士将评估Pex 7 p表达、亚细胞定位 和介导PTS 2蛋白输入的能力。她还将决定 Pex 7 p结合PTS 2并与其他过氧化物相互作用。这些研究将 定义PTS 2蛋白导入的步骤，并允许PEX 7缺陷的相关性 RCDP表型的变异。私家侦探将产生一个小鼠模型， RCDP研究PTS 2蛋白途径的生化改变， 与组织病理学的关系。拟议的战略将利用cre/lox 工程化亚纯型、无效和条件性PEX 7等位基因的技术， 产生具有这些等位基因的组合的小鼠，以开发有用的 RCDP。这些小鼠将通过临床、放射学、组织学 和生化评估。这些信息将有助于理解 RCDP的病理生理学以及过氧化物酶体的正常生物学 在骨、透镜和CNS发育中的组装和功能。

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.