Mutations disrupting ciliary assembly and trafficking are a common cause of inherited retinal degenerations, causing early-onset severe blindness. Bardet-Biedl syndrome (BBS) is one of the human genetic diseases associated with defective ciliary trafficking and photoreceptor degeneration. However, details of the patho-mechanisms underlying photoreceptor degeneration in BBS are largely unknown and no effective treatment options have been developed. The long-term goal of this research program is to elucidate the molecular and cellular mechanisms of photoreceptor degeneration in BBS and develop therapeutic interventions to preserve vision in BBS patients. Our prior study determined that accumulation of proteins in the outer segment (OS) is likely the primary cause of photoreceptor degeneration in BBS, representing a novel mechanism of photoreceptor degeneration. During the next grant cycle, we will explore how protein accumulation in the OS induces photoreceptor degeneration. Our preliminary data suggest that OS accumulation/sequestration of Stx3 (a SNARE protein facilitating membrane fusion events) and proteasomal overload stress are involved. The proposed study will determine how these factors contribute to photoreceptor degeneration in BBS. The outcome of this study will greatly advance our understanding of the cilia-related retinopathies and provide an important foundation for the development of mechanism-based therapies.
Inherited retinal degenerations due to defective protein trafficking in photoreceptor cells causes severe blindness in children and young adults, but no treatment options are available. In the proposed study, we will determine the mechanisms of retinal degeneration in Bardet-Biedl syndrome (BBS), a human genetic disease associated with defective protein trafficking. This study will provide critical insights into the mechanisms of photoreceptor degeneration and open up new treatment strategies for BBS and potentially other inherited retinal degenerations that share common disease mechanisms.
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