Healthy rod and cone photoreceptors are essential for human vision. There are numerous diseases that cause these cells to die or function improperly, resulting in blindness or visual impairment. Thus, it is of prime importance to fully characterize the fundamental aspects of their cellular and molecular biology. Two crucial cellular processes that require more intense study are the molecular mechanisms that 1) regulate transcription in photoreceptors, particularly cones, and 2) underlie the proper sorting of rod-specific proteins. Xenopus offers a unique experimental system in which to ask fundamental questions about photoreceptor function and dysfunction. ? ? We propose two specific aims: ? ? Aim 1. Regulation of gene transcription in photoreceptors: the molecular basis for cone specific gene expression. ? a. Characterize the cis-elements in the cone-specific L-opsin promoter. ? b. Identify transcription factors that bind to cis regulatory elements. ? ? Aim 2. The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in autosomal dominant retinitis pigmentosa. ? a. Characterize the UPR/ER stress response in transgenic Xenopus expressing the autosomal dominant rhodopsin mutant, P23H. ? b. Characterize the UPR/ER stress response in Rho(P23H) transgenic mice. ? ? Significance: This proposal addresses two long standing questions in photoreceptor biology: how is cone-specific gene expression regulated and what is the mechanism by which mutant rhodopsin kills rods? We intend to identify transcription factors regulating cone-specific gene expression. These proteins play a critical role in retinal development and their mutation or dysfunction may result in photoreceptor death. Rho(P23H) has folding abnormality that causes cell death. To understand and treat adRP, a better understanding of how photoreceptors react to the mutant protein at the molecular level is needed. Once the relevant signaling pathway(s) are identified, it may be possible to therapeutically target the signaling pathways to slow or block disease progression. ? ? ?
Showing the most recent 10 out of 37 publications
