Photoreceptor cell degeneration in D. melanogaster

黑腹果蝇感光细胞变性

• 批准号: 6823262
• 负责人: PATRICK J. DOLPH
• 金额: $ 29.23万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823262
• 关键词: Drosophilidae; apoptosis; arrestins; genetic screening; laboratory rabbit; protein binding; protein protein interaction; receptor mediated endocytosis; retina degeneration; rhodopsin; visual photoreceptor; visual phototransduction; western blottings

DESCRIPTION (provided by applicant): In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the phototransduction cascade. The inactivation of the cascade at one level is achieved by the binding of the regulatory protein arrestin to rhodopsin. The normally transient interaction between rhodopsin and arrestin is stabilized in certain genetic backgrounds where arrestin remains in the unphosphorylated form. The accumulation of these stable complexes between rhodopsin and arrestin are direct mediators of photoreceptor cell apoptosis and retinal degeneration. The initial step in photoreceptor cell degeneration is the internalization of the rhodopsin/arrestin complexes into the cell body via receptor-mediated endocytosis. The rhodopsin accumulates in insoluble aggregates within the photoreceptor cytoplasm. This defines a novel apoptotic signaling pathway that is responsible for retinal degeneration in a number of Drosophila mutants. Interestingly, in several different forms of autosomal dominant retinitis pigmentosa stable complexes between rhodopsin and arrestin have been observed. Moreover, many neuronal degenerative disorders are characterized by the intracellular accumulation of protein complexes, suggesting that this may be a common apoptotic mechanism that is used in a wide variety of diseases. In an effort to further characterize this novel apoptotic pathway three experimental approaches will be undertaken. 1). We will determine if an interaction between arrestin and the AP2 heterotetramer is essential for rhodopsin endocytosis. 2). We will examine the role of endosomal trafficking of rhodopsin and arrestin in the activation of cell death. 3). A genetic screen will be conducted to isolate gene products involved in this novel apoptotic signaling pathway. Gene products involved in coupling rhodopsin/arrestin complex formation with the cell death machinery will be identified and characterized.

描述（由申请人提供）：在视觉系统中，通过光的光子激活Rhodopsin会引发一系列事件，称为光转录级联。通过调节蛋白阻滞蛋白与视紫红质的结合，级联反应在一个水平上的失活。在某些遗传背景中，在某些遗传背景中稳定了视紫红质和抑制蛋白之间的瞬时相互作用，在这些遗传背景中，抑制蛋白保持未磷酸化形式。这些稳定的复合物在视紫红质和阻滞蛋白之间的积累是感光细胞细胞凋亡和视网膜变性的直接介体。光感受器细胞变性的第一步是通过受体介导的肠细胞增多症将视紫红质/阻滞蛋白复合物的内在化进入细胞体。视紫红蛋白在光感受器细胞质内积聚在不溶性聚集体中。这定义了一种新型的凋亡信号通路，该通路负责许多果蝇突变体中的视网膜变性。有趣的是，在几种不同形式的常染色体显性视网膜炎色素色素稳定的复合物中，观察到了视紫红质和抑制素之间的稳定复合物。此外，许多神经元退化性疾病的特征是蛋白质复合物的细胞内积累，这表明这可能是一种常见的凋亡机制，用于多种疾病。 为了进一步表征这种新型凋亡途径，将采用三种实验方法。 1）。我们将确定抑制蛋白和AP2异驱动剂之间的相互作用对于视紫红质内吞作用至关重要。 2）。我们将研究视紫红蛋白的内体贩运和抑制蛋白在细胞死亡激活中的作用。 3）。将进行遗传筛选，以分离涉及这种新型凋亡信号通路中的基因产物。将确定并表征与细胞死亡机器偶联的基因产物与细胞死亡机械的形成。