PEX7 AND IT'S ROLE IN THE PATHOGENESIS OF RCDP

描述(改编自研究人员摘要)：根状软骨发育不良 斑点状(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，严重的发育障碍和智力低下。RCDP是 遗传为常染色体隐性遗传，由PEX7突变引起， 该基因编码Pex7p，Pex7p是过氧化物酶的受体，具有pts2 序列。将pts2蛋白导入到 过氧酶体尚不清楚，但P.I.倾向于Pex7p结合的模型 胞浆中的pts2蛋白，并将它们运输到过氧化物体。Pex7p 包含六个确定贝塔螺旋桨的WD40主题，这种结构 为蛋白质相互作用提供多个刚性表面。在RCDP中，有缺陷 Pts2酶的功能被认为会产生未知的代谢变化。 决定RCDP表型的基因。这项提案的总体目标是 研究Pex7p的分子和细胞生物学以及RCDP的发病机制。 P.I.将通过对疾病的识别和功能分析来实现这一点 50+RCDP先证者相关PEX7基因突变及野生型的功能分析 键入Pex7p。Braverman博士将评估Pex7p的表达、亚细胞定位 以及介导pts2蛋白输入的能力。她还将确定地区 与pts2结合并与其他过氧化物素相互作用的Pex7p。这些研究将 定义pts2蛋白导入的步骤，并允许PEX7缺陷的关联 RCDP表型的变异。私家侦探将产生一种小鼠模型 RCDP研究PTS2蛋白通路的生化变化和 它们与组织病理学的关系。拟议的战略将利用cre/lox。 改造亚形、空和条件性PEX7等位基因和 用这些等位基因的组合产生小鼠，以开发有用的模型 RCDP。这些小鼠的临床、放射学、组织学特征 和生化评估。这些信息将有助于理解 RCDP的病理生理学及过氧化物酶体的正常生物学 在骨骼、晶状体和中枢神经系统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.