Research Project
8676804
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.
