CILIA IN EYE DEVELOPMENT AND DISEASE

纤毛与眼睛发育和疾病的关系

• 批准号: 8258716
• 负责人: JAREMA MALICKI
• 金额: $ 26.7万
• 依托单位: UNIVERSITY OF SHEFFIELD
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258716
• 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; public health relevance; 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）：本研究计划重点关注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育、分化和功能至关重要。在脊椎动物的眼睛中，感光细胞的感光部分，即所谓的外节，形成高度分化的纤毛。在没有纤毛轴丝的情况下，外节不会形成，光感受器没有功能，并且会退化。较轻微的纤毛缺陷经常导致感光细胞中视觉色素的错误定位。这是一个严重的缺陷，已知会导致光感受器死亡。许多形式的人类失明都与纤毛功能障碍有关。肾痨 (NPHP) 和梅克尔-格鲁伯综合征 (MKS) 是纤毛性疾病，除了其他异常之外，还涉及光感受器变性和失明。尽管已经鉴定出一些 NPHP 和 MKS 基因，但它们的蛋白质产物在细胞中的功能却知之甚少（如果有的话）。我们假设 NPHP 和 MKS 蛋白有助于将视色素运输到感光器外节。因此，它们的缺陷导致视觉色素错误定位和光感受器死亡。使用生化和遗传学方法，我们确定了 MKS 以及 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 MKS 和 NPHP 蛋白如何促进光感受器外节中的视蛋白运输。对携带 NPHP 和 MKS 缺陷的人类的研究发现了许多导致光感受器死亡的分子缺陷。然而，这些损伤如何影响蛋白质功能仍然未知。我们将测试人类突变如何影响 NPHP 和 MKS 蛋白定位于纤毛并结合其伴侣的能力。与上述实验一起，这些研究将揭示光感受器形态发生、功能和生存所必需的基本机制。他们还将提供一种方法来测试人类突变对感光细胞中蛋白质功能特定方面的影响。 公共卫生相关性：纤毛对于光感受器分化和存活是必需的。它们的故障经常导致失明。几种形式的综合征性遗传性失明，包括肾病（NPHP）、梅克尔-格鲁伯综合征（MKS）和巴代-比德尔综合征（BBS）都与纤毛功能障碍有关。该项目将促进人们对与这些疾病相关的基因如何在感光细胞中发挥作用的理解。