EXCEED THE SPACE PROVIDED. Choroideremia (CHM) is an X-linked disease of the eye that leads to degeneration of the choriocapillarisand adjoining retinal pigment epithelium (RPE) and photoreceptor layers. The responsible gene product, CHM, is 'Rab escort protein' (REP1). CHM/REP1 is the component A subunit of Rab geranylgeranyl transferase II that delivers newlysynthesized Rab GTPases to the catalytic complex (component B) for post-translational prenylation. Rab proteins required for membrane vesicular traffic through the exocytic and endocytic pathways. As outlined in the National Plan forVision Research, we will, as a primary goal, determine the pathophysiological mechanisms underlyingloss of function of CHM/REP1 function retinal degenerative diseases. As highly related objectives we will identify the novel cause of inherited retinal degeneration mediated by CHM/REP1 by specifically examining the cellular and molecular mechanisms regulated in response to this specific gene defect and probe the retina's microenvironment through studies understanding the function of CHM/REP1 in controlling the ability of the RPE to interact with photoreceptor and other cells in the choriocapillus. The following specific aims will provide insight into the physiological role of CHM/REP1 in the retina and in retinal degeneration.
In Specific Aim 1, we will examine the hypothesis that CHM/REP1 dysfunction in choroideremia is a direct consequence of defects in the vesicular transport pathways in RPE regulated by Rab GTPases that are uniquely prenylated by CHM/REP1. These include pathways involved in the establishment and maintenance of cell polarity of RPE cells, in the biogenesis and delivery of vitamin A to photoreceptor cells, or in phagocytic pathways essential for clearance of photoreceptor outer segments (ROS) shed into the subretinal space.
In Specific Aim 2, we will generate Rab27 mutants to understand the basis for specific recognition of CHM/REP1 and to understand the function of Rab27 in vesicular traffic in RPE cells.
In Specific Aim 3, we will address the physiological basis for CHM/REP1 dysfunction in choroideremia by generating conditional transgenic mouse lines using the lox-Cre recombinase system. We will use these to explore CHM/REP1 function in the visual system. These three specific aims, when combined with our ongoing work on the high resolution structural analysisof the CHM/REP1 protein and its complex with Rab, will provide new insight into the role of prenylation of specific Rab proteins in retinal degenerative diseases. These studies are anticipated to provide insight into the development of new therapeutic approaches to normalize function in the diseased state by stabilizingthe RPE and adjacent choriocapillaris and photoreceptor layers in their differentiated states. PERFORMANCE SITE ========================================Section End===========================================
