Photoreceptor degeneration is a major cause of early onset blindness. Accumulating evidence indicates that mutations in ciliary trafficking genes are one of the most common causes of inherited photoreceptor degeneration. Yet, the underlying mechanisms of photoreceptor degeneration due to defective ciliary trafficking are poorly understood. The long-term objective of the proposed research is to advance therapeutic potential by understanding the molecular mechanisms of photoreceptor degeneration associated with defective ciliary trafficking. Bardet-Biedl Syndrome (BBS) is a human genetic disorder associated with ciliary trafficking defects that leads to photoreceptor degeneration. Recently, we and others have shown that BBS proteins are involved in the transport of specific cargo proteins between the ciliary and plasma membranes and that identification of BBS protein cargos has significant implications for the etiology of BBS. Here, we hypothesize that BBS proteins transport specific cargo proteins between the inner and outer segments of the photoreceptor cells and that the trafficking defects of these cargos underlie the pathophysiology of retinal degeneration. In this project, we will identify BBS protein cargos in the photoreceptor cells and advance our understanding of the underlying molecular mechanisms of photoreceptor degeneration in BBS by pursuing the following specific aims: 1) Identify BBSome cargos and regulators using transgenic mice and tandem affinity purification, 2) Perform quantitative proteomic analysis of photoreceptor outer segments from BBS retina using iTRAQ, and 3) Elucidate the biological significance of BBSome cargos and regulators with respect to disease mechanisms. In preliminary studies, we isolated and identified BBSome interacting proteins from several tissues relevant to BBS. We also found that several proteins that are associated with retinitis pigmentosa or Leber congenital amaurosis are decreased in the BBS outer segment. We will further extend these findings and elucidate the molecular basis of photoreceptor degeneration in BBS. This research will ultimately provide valuable insight into the basic biological mechanisms by which BBS proteins maintain normal photoreceptor cell function and also serve as a knowledge base for the development of mechanism-based therapies for ciliopathy-related retinal degenerations.
Inherited retinal degenerations are one of the major causes of early onset blindness. These disorders are often caused by a loss of proteins that are involved in protein transport to primary cilia. The proposed research will provide insight into the molecula mechanisms of retinal degeneration caused by mutations in ciliary trafficking genes, so that therapies can be developed to prevent vision losses due to these diseases.
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|Chamling, Xitiz; Seo, Seongjin; Searby, Charles C et al. (2014) The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome. PLoS Genet 10:e1004083|
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|Seo, Seongjin; Solivan-Timpe, Frances; Roos, Ben R et al. (2013) Identification of proteins that interact with TANK binding kinase 1 and testing for mutations associated with glaucoma. Curr Eye Res 38:310-5|