About 5% of human Retinitis Pigmentosa (RP) and 10% of Leber Congenital Amaurosis (LCA) are caused by mutations in the extracellular domain of the apical polarity protein Crumbs1 (CRB1). However, the detailed molecular etiologies of CRB1-related RP and LCA are unclear. Zebrafish retina is a very good vertebrate model to study human retinal degeneration diseases because zebrafish and human retinas are similar in both tissue structure and function. For example, zebrafish retinal development and maintenance also require Crb proteins. Previously, we discovered that zebrafish Crb2a and Crb2b play important roles in cone mosaic pattern formation and in cone survival; in addition, Crb1 is also expressed in the retina. However, we still need to decipher the molecular mechanisms by which Crb carry out their functions as well as how dysfunction of Crb proteins contributes to photoreceptor degeneration. To better understand the retinal functions of Crb proteins, we here propose to investigate the following questions: the mechanisms by which Crb1 and Crb2a/2b localize to different subcellular regions, the functions of Crb for photoreceptor outer segment development, and the Crb-based molecular mechanism of photoreceptor maintenance. The completion of this research will take us one step closer to reaching our long-term goal of finding effective treatments for human retinal degenerative conditions caused by malfunctions of polarity proteins.
Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA) are among the many retinal degenerative diseases that affect millions of people. The proposed research will help us to better understand the molecular etiologies of CRB1-related human RP and LCA diseases. The study may also provide clues to the etiologies of other retinal degenerative diseases. Ultimately, this research will contribute to finding effective treatments fo human retinal degenerative conditions.
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