Retinal Epithelial Polarity and Cellular Patterning:Crbs and their associates

描述(申请人提供)：视网膜色素变性(RP)和Leber先天性黑色素沉着症(LCA)是影响数百万人的许多视网膜退行性疾病之一。RP和LCA可由许多基因的故障引起，例如人类Crums1(CRB1)基因。CRB1相关的RP和LCA的详细分子病因学尚不清楚。这项建议的目的是检验一个总体假设，即适当的靶向和功能的Crb2a和Crb2b复合体在光感受器发育中发挥重要作用。我们建议使用斑马鱼来模拟CRB同源物及其相关蛋白如何在视网膜发育中发挥作用，以及人类CRB1基因的致病突变如何影响其功能。在斑马鱼中，三种CRB蛋白(Crb1、Crb2a和Crb2b)在光感受器层表达。我们提出了三个目标。首先，测试一种假设，即Crb2a介导了一种新型的光感受器-光感受器(P-P)黏附，这种黏附可以受到Crb2a突变的影响，该突变相当于人类CRB1中已发现的隐性致病突变。第二，验证由Crb2b介导的P-P黏附对感光细胞存活和构图至关重要的假设。我们还将测试相当于人类CRB1基因突变的Crb2b突变是否会导致视网膜退化。第三，验证Ponli蛋白的时空调节对某些锥体的形态发生至关重要的假设。这项拟议的研究将为光感受器图案的形成和光感受器层的维持提供见解。此外，它还将提高对某些人类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，找到治疗人类视网膜退行性疾病的有效方法。 公共卫生相关性：视网膜色素变性(RP)和Leber先天性黑色素沉着症(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疾病的分子病因学，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.