CILIA IN EYE DEVELOPMENT AND DISEASE

纤毛与眼睛发育和疾病的关系

• 批准号: 8108186
• 负责人: JAREMA MALICKI
• 金额: $ 37.91万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8108186
• 关键词: Affect; Apical; Bardet-Biedl Syndrome; Binding; Biochemical Genetics; Blindness; C-terminal; Carrier Proteins; Cells; Cessation of life; Cilia; Complex; Data; Defect; Degenerative Disorder; Development; Disease; Eye; Eye Development; Eye diseases; Gene Proteins; Genes; Goals; Heat-Shock Response; Human; Integral Membrane Protein; Kinesin; Knowledge; Lead; Lesion; Life; Mediating; Membrane; Microtubules; Molecular; Molecular Motors; Morphogenesis; Motor; Movement; Mutation; Nephronophthisis; Opsin; Photoreceptors; Phototransduction; Physiologic pulse; Protein Binding; Proteins; Research; Research Proposals; Retinal Pigments; Role; Route; Structure; Syndrome; System; Tail; Testing; Tissues; Vertebrate Photoreceptors; constriction; gene function; hereditary blindness; kinetosome; neuronal cell body; novel strategies; particle; peripherin; photoreceptor degeneration; polypeptide; promoter; protein complex; protein function; protein protein interaction; protein transport; research study

DESCRIPTION (provided by applicant): This research proposal focuses on the role of cilia in photoreceptor morphogenesis. Cilia are essential for development, differentiation, and function of many tissues. In the vertebrate eye, the photosensitive part of the photoreceptor cell, the so-called outer segment, forms as a highly differentiated cilium. In the absence of ciliary axoneme, the outer segment does not form, the photoreceptor is not functional, and it degenerates. Milder cilia defects frequently cause the visual pigment mislocalization in the photoreceptor cell. This is a serious defect, known to cause photoreceptor death. Many forms of human blindness involve cilia malfunction. Nephronophthisis (NPHP) and Meckel-Gruber syndrome (MKS) are ciliary disorders that in addition to other abnormalities involve photoreceptor degeneration and blindness. Although several NPHP and MKS genes have been identified, the function of their protein products in the cell is poorly understood, if at all. We hypothesize that NPHP and MKS proteins contribute to the transport of the visual pigment to the photoreceptor outer segment. Accordingly, their defects lead to visual pigment mislocalization and photoreceptor death. Using biochemical and genetic approaches, we identified binding interactions between MKS as well as NPHP proteins and molecular complexes involved in ciliary protein transport. Here we propose to study these interactions further, and to test how MKS and NPHP proteins contribute to opsin transport in the photoreceptor outer segment. The studies of human carries of NPHP and MKS defects identified many molecular liesions that cause photoreceptor death. How do these lesions affect protein function remains, however, unknown. We will test how human mutations impact the ability of NPHP and MKS proteins to localize to cilia and to bind their partners. Together with experiments outlined above, these studies will reveal fundamental mechanisms, necessary for photoreceptor morphogenesis, function, and survival. They will also offer a way to test the impact of human mutations on specific aspects of protein function in the photoreceptor cell. PUBLIC HEALTH RELEVANCE: Cilia are necessary for photoreceptor differentiation and survival. Their malfunction frequently results in blindness. Several forms of syndromic hereditary blindness, including Nephronopthisis (NPHP), Meckel-Grueber Syndromethe (MKS), and Bardet-Biedl Syndrome (BBS) are associated with cilia malfunction. This project will advance the understanding of how genes involved in these diseases function in the photoreceptor cell.

描述（由申请人提供）：该研究提案的重点是纤毛在光感受器形态发生中的作用。纤毛对于许多组织的发展，分化和功能至关重要。在脊椎动物的眼中，感光细胞的光敏部分（所谓的外部段）形成是高度分化的纤毛。在没有睫状轴突的情况下，外部段未形成，光感受器不起作用，并且会退化。温和的纤毛缺陷经常引起感光细胞中视觉色素错误定位。这是一个严重的缺陷，已知会导致感光者死亡。许多形式的人类失明涉及纤毛故障。肾植物（NPHP）和梅克尔 - 克鲁伯综合征（MK）是纤毛疾病，除其他异常外，还涉及光感受器退化和失明。尽管已经鉴定出了几种NPHP和MKS基因，但如果有的话，它们在细胞中蛋白质产物的功能知之甚少。我们假设NPHP和MKS蛋白有助于将视觉色素传输到感光器外部段。因此，它们的缺陷导致视觉色素不定位和光感受器死亡。使用生化和遗传方法，我们确定了MKS，NPHP蛋白和参与纤毛蛋白转运的分子复合物之间的结合相互作用。在这里，我们建议进一步研究这些相互作用，并测试MK和NPHP蛋白如何在光感受器外部节段中促进Opsin转运。 NPHP和MKS缺陷的人类携带的研究确定了导致感光器死亡的许多分子谎言。然而，这些病变如何影响蛋白质功能。我们将测试人类突变如何影响NPHP和MKS蛋白将其定位为纤毛并束缚其伴侣的能力。与上面概述的实验一起，这些研究将揭示基本机制，这是光感受器形态发生，功能和生存所必需的。他们还将提供一种测试人类突变对感光细胞中蛋白质功能特定方面的影响的方法。 公共卫生相关性：纤毛对于光感受器的分化和生存是必需的。他们的故障经常导致失明。包括肾上腺素症（NPHP），Meckel-Grueber综合症（MKS）和Bardet-Biedl综合征（BBS）在内的几种形式的综合症遗传失明与纤毛故障有关。该项目将促进对这些疾病中涉及的基因在感光细胞中的作用的理解。