PROJECT SUMMARY/ABSTRACT The long-term goal of our research is to identify mechanisms that contribute to the maintenance of photoreceptor outer segments and vision. In retinal degenerative blinding diseases, loss of ciliated photoreceptor outer segments precedes the death of photoreceptor neurons. Therefore, a thorough understanding of the mechanisms behind the stability of the cilia is needed to uncover molecules required for photoreceptor survival. The specific goal of this proposal is to identify the importance of post-translational modifications of tubulins in the maintenance of cilia and photoreceptor function. Altered tubulin modifications are a known cause of human blindness. We will investigate the need for a small GTPase that belongs to the ARF-like family of proteins, ARL13B, and its role in photoreceptor ciliary maintenance, tubulin modifications, and function. Our studies will investigate whether altering tubulin modifications will protect photoreceptors and rescue visual response in various genetic models for retinal degenerative diseases. We will use a combination of unique animal models, cell culture models, and in vitro biochemical analyses to comprehensively address the requirement for tubulin modification and their regulation in ciliated photoreceptors. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to “Elucidate the molecular mechanisms that lead to photoreceptor degeneration, including signal transduction pathways, defects in protein folding, ciliogenesis, functional compartmentalization, or trafficking, and translate these molecular footholds into therapies for Mendelian and complex diseases.” The findings from the proposed studies have clinical implications, such as therapy for inherited retinal diseases that lead to blindness.

PROJECT NARRATIVE This project will identify the importance of tubulin modifications and the small GTPase ARL13B in the health of light-sensing photoreceptor cells. With a thorough understanding of the basic biology behind photoreceptor health, we hope to identify novel therapies for patients with inherited blindness.