Retinal Epithelial Polarity and Cellular Patterning:Crbs and their associates

描述（由申请人提供）：视网膜色素变性（RP）和利伯先天性黑蒙（LCA）是影响数百万人的许多视网膜退行性疾病之一。RP和LCA可以由许多基因的功能障碍引起，例如人类Crumbs 1（CRB 1）基因。CRB 1相关RP和LCA的详细分子病因尚不清楚。该提案的目的是测试一个总体假设，即Crb 2a和Crb 2b复合物的适当靶向和功能在感光细胞发育中起重要作用。我们建议使用斑马鱼来模拟Crb同源物及其相关蛋白在视网膜发育中的作用以及人类CRB 1基因的致病突变如何影响其功能。在斑马鱼中，三种Crb蛋白（Crb 1、Crb 2a和Crb 2b）在感光层中表达。我们提出了三个目标。首先，检验Crb 2a介导一种新型光感受器-光感受器（P-P）粘附的假设，该粘附可受到Crb 2a突变的影响，该突变相当于人类CRB 1中已鉴定的隐性致病突变。第二，检验由Crb 2b介导的P-P粘附对于光感受器存活和图案化是必不可少的这一假设。我们还将测试Crb 2b中的突变与人类CRB 1中已鉴定的突变等同，可导致视网膜变性。第三，检验Ponli蛋白的空间和时间调节对于某些视锥细胞的形态发生至关重要的假设。这项研究将为感光体图案的形成和感光体层的维持提供深入的了解。此外，它将提高对某些人类RP和LCA疾病的分子病因学的理解，并为其他视网膜变性疾病提供线索。我们的长期目标是通过破译视网膜细胞模式形成的分子和细胞机制来找到有效的治疗人类视网膜变性的方法。 公共卫生相关性：视网膜色素变性（RP）和Leber先天性黑蒙（LCA）是影响数百万人的许多视网膜退行性疾病之一。这项研究将有助于我们更好地了解某些人类RP和LCA疾病的分子病因，并为其他视网膜退行性疾病提供线索。最终，这项研究将帮助我们实现破译视网膜细胞模式形成的分子和细胞机制的长期目标，并利用这些知识为人类视网膜退行性疾病找到有效的治疗方法。

DESCRIPTION (provided by applicant): Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are among the many retinal degenerative diseases that affect millions of people. RP and LCA can be caused by malfunction of many genes, such as the human Crumbs1 (CRB1) gene. The detailed molecular etiology of CRB1-related RP and LCA is unclear. The objective of this proposal is to test an overall hypothesis that proper targeting and functioning of Crb2a and Crb2b complexes play essential roles in photoreceptor development. We propose to use zebra fish to model how Crb homologs and their associated proteins play roles in retinal development and how pathogenetic mutations in human CRB1 gene affect its functions. In zebra fish three Crb proteins (Crb1, Crb2a, and Crb2b) are expressed in the photoreceptor layer. We proposed three aims. First, test the hypothesis that Crb2a mediate a novel type of photoreceptor-photoreceptor (P-P) adhesion, which can be affected by a Crb2a mutation that is equivalent to an identified recessive pathogenetic mutation in human CRB1. Second, test the hypothesis that P-P adhesion mediated by Crb2b is essential for photoreceptor survival and patterning. We will also test that a mutation in Crb2b that is equivalent to an identified mutation in human CRB1 can cause retinal degeneration. Third, test the hypothesis that spatial and temporal regulation of the Ponli protein is essential for the morphogenesis of certain cones. The proposed research will provide insights into photoreceptor pattern formation and the maintenance of the photoreceptor layer. In addition, it will improve understanding of the molecular etiology of certain human RP and LCA diseases and provide clues to other retinal degeneration diseases. Our long-term goal is to find effective treatments for human retinal degeneration conditions by deciphering the molecular and cellular mechanisms of retinal cellular pattern formation. PUBLIC HEALTH RELEVANCE: Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are among the many retinal degenerative diseases that affect millions of people. The proposed research will help us to better understand the molecular etiology of certain human RP and LCA diseases and to provide clues to other retinal degenerative diseases as well. Ultimately, the study will assist us in reaching the long-term goal of deciphering the molecular and cellular mechanisms of retinal cellular pattern formation and using such knowledge for finding effective treatments for human retinal degenerative conditions.