Crumbs proteins for photoreceptor development and health maintenance

用于光感受器发育和健康维护的碎屑蛋白质

• 批准号: 9105969
• 负责人: XIANGYUN WEI
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105969
• 关键词: Adhesions; Affect; Apical; Binding; CRISPR/Cas technology; Cell Proliferation; Cell membrane; Cone; Data; Degenerative Disorder; Development; Disease; Etiology; Extracellular Domain; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic Epistasis; Goals; Health; Human; Hybrids; Individual; Leber' s amaurosis; Maintenance; Mechanics; Mediating; Modeling; Molecular; Morphogenesis; Muller' s cell; Mutagenesis; Mutation; One-Step dentin bonding system; PDZ protein; Pattern Formation; Photoreceptors; Play; Process; Proteins; Research; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Role; Signal Pathway; Signal Transduction; Structure; Technology; Testing; Tissues; Variant; Vertebrate Photoreceptors; Zebrafish; base; cell type; cofactor; effective therapy; fovea centralis; in vivo; intercellular communication; mouse model; novel; photoreceptor degeneration; public health relevance; therapeutic target

 DESCRIPTION (provided by applicant): About 5% of human Retinitis Pigmentosa (RP) and 10% of Leber Congenital Amaurosis (LCA) are caused by mutations in the extracellular domain of the apical polarity protein Crumbs1 (CRB1). However, the detailed molecular etiologies of CRB1-related RP and LCA are unclear. Zebrafish retina is a very good vertebrate model to study human retinal degeneration diseases because zebrafish and human retinas are similar in both tissue structure and function. For example, zebrafish retinal development and maintenance also require Crb proteins. Previously, we discovered that zebrafish Crb2a and Crb2b play important roles in cone mosaic pattern formation and in cone survival; in addition, Crb1 is also expressed in the retina. However, we still need to decipher the molecular mechanisms by which Crb carry out their functions as well as how dysfunction of Crb proteins contributes to photoreceptor degeneration. To better understand the retinal functions of Crb proteins, we here propose to investigate the following questions: the mechanisms by which Crb1 and Crb2a/2b localize to different subcellular regions, the functions of Crb for photoreceptor outer segment development, and the Crb-based molecular mechanism of photoreceptor maintenance. The completion of this research will take us one step closer to reaching our long-term goal of finding effective treatments for human retinal degenerative conditions caused by malfunctions of polarity proteins.

 描述（由申请人提供）：约5%的人类色素性视网膜炎（RP）和10%的Leber先天性黑蒙（LCA）是由顶端极性蛋白Crumbs 1（CRB 1）的细胞外结构域突变引起的。然而，CRB 1相关RP和LCA的详细分子病因尚不清楚。由于斑马鱼和人类视网膜在组织结构和功能上都很相似，因此斑马鱼视网膜是研究人类视网膜变性疾病的非常好的脊椎动物模型。例如，斑马鱼视网膜的发育和维持也需要Crb蛋白。在此之前，我们发现斑马鱼Crb 2a和Crb 2b在视锥镶嵌图案形成和视锥存活中起重要作用;此外，Crb 1也在视网膜中表达。然而，我们仍然需要破译Crb执行其功能的分子机制，以及Crb蛋白的功能障碍如何导致感光细胞退化。为了更好地了解Crb蛋白在视网膜中的功能，我们在这里提出了以下问题：Crb 1和Crb 2a/2b定位于不同的亚细胞区域的机制，Crb的感光细胞外节发育的功能，以及基于Crb的感光细胞维持的分子机制。这项研究的完成将使我们更接近于实现我们的长期目标，即找到有效治疗由极性蛋白质故障引起的人类视网膜退行性疾病的方法。