Molecular Mechanisms of Photoreceptor Function

光感受器功能的分子机制

• 批准号: 7318553
• 负责人: Barry E Knox
• 金额: $ 31.4万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318553
• 关键词: Address; Binding; Biology; Blindness; Cell Death; Cell physiology; Cells; Cessation of life; Condition; DNA Sequence; Development; Disease; Disease Progression; Elements; Endoplasmic Reticulum; Functional disorder; Gene Expression; Genetic Transcription; Human; Indium; Life; Molecular; Molecular and Cellular Biology; Mutation; Numbers; Opsin; Photoreceptors; Play; Principal Investigator; Proteins; Regulation; Regulatory Element; Retinal; Retinal Cone; Retinitis Pigmentosa; Rhodopsin; Role; Signal Pathway; Sorting - Cell Movement; Stress; Stress Response Signaling; System; Technology; Testing; Time; Transgenic Mice; Transgenic Organisms; Vertebrate Photoreceptors; Vision; Visual impairment; Xenopus; base; biological adaptation to stress; coping; in vivo; killings; mutant; novel; novel strategies; programs; promoter; protein folding; response; retinal rods; rho; transcription factor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：健康的棒和锥形感光体对于人类视力至关重要。有许多疾病会导致这些细胞死亡或不正常地发挥作用，从而导致失明或视觉障碍。因此，完全表征其细胞和分子生物学的基本方面是至关重要的。需要更激烈研究的两个至关重要的细胞过程是分子机制，即1）调节光感受器（尤其是锥体）中的转录，以及2）基于正确分类杆特异性蛋白的基础。 Xenopus提供了一个独特的实验系统，在其中询问有关光感受器功能和功能障碍的基本问题。 我们提出了两个具体目标： 目标1。光感受器中基因转录的调节：锥体特异性基因表达的分子基础。 一个。表征锥体特异性L-粘着蛋白启动子中的顺式元素。 b。确定与顺式调节元件结合的转录因子。 AIM 2。内质网应激的作用和未折叠的蛋白质反应（UPR）在常染色体显性视网膜炎色素炎中的作用。 一个。表征了表达常染色体显性视紫红质突变体P23H的转基因爪蟾中的UPR/ER应力反应。 b。表征RHO（P23H）转基因小鼠中的UPR/ER应力反应。 意义：该提案解决了光感受器生物学中的两个长期问题：锥体特异性基因表达如何调节，突变型动蛋白杀死杆的机制是什么？我们打算确定调节锥体特异性基因表达的转录因子。这些蛋白质在视网膜发育中起关键作用，它们的突变或功能障碍可能导致感光器死亡。 RHO（P23H）的折叠异常会导致细胞死亡。为了理解和治疗ADRP，需要更好地理解光感受器如何在分子水平上对突变蛋白的反应。一旦确定了相关的信号通路，就有可能以治疗方法靶向信号通路，以缓慢或阻止疾病进展。