The long-term goal of this project is to improve both the diagnoses and the treatments of Leber congenital amaurosis (LCA). LCA is a set of inherited, early onset retinopathies that affect about 1 in 50,000 in the general U.S. population and accounts for more than 5% of all retinal dystrophies. The molecular basis for LCA is heterogeneous with mutations in 22 different genes that have been associated with the disease. Strikingly, ciliopathy has been identified as one of the major causes of LCA with 25% of the known disease- causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently identified that Spata7, a ciliopathy gene, maintains a photoreceptor- specific transition zone (PSTZ), which is a specialized structure in photoreceptor connecting cilia and plays a critical role in protein trafficking. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel PSTZ zone in the connecting cilium of photoreceptor cells.
Our Specific Aims are to:
Specific Aim 1 : Define and characterize two novel zones of the connecting cilium.
Specific Aim 2. Determine the mechanism of SPATA7 action in RPGR complex assembly and function in the distal TZ of photoreceptor cilia.
Specific Aim 3 : Determine the role of Spata7 in PSTZ structure and function. Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.
The main goal of this project is to create a model of the human retinal disease called Leber congenital amaurosis (LCA), which is the leading cause of blindness in infants. In order to create more effective means of diagnosis, prevention, and treatment, we need a more detailed understanding of this devastating disease. Our model for LCA using the mouse will provide an essential platform for determining the exact defects and potential therapies to correct such defects.
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