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Photoreceptor cell degeneration in D. melanogaster

黑腹果蝇感光细胞变性

基本信息

批准号：
7152941
负责人：
PATRICK J. DOLPH
金额：
$ 27.72万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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

项目摘要

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，光光子激活视紫质会引发一系列称为光转导级联的事件。一级级联的失活是通过调节蛋白视紫红质与视紫红质的结合来实现的。视紫红质和视紫红质抑制蛋白之间通常短暂的相互作用在某些遗传背景下稳定，其中视紫质抑制蛋白保持非磷酸化形式。视紫红质和视紫红质抑制蛋白之间这些稳定复合物的积累是感光细胞凋亡和视网膜变性的直接介质。感光细胞变性的第一步是视紫红质/抑制蛋白复合物通过受体介导的内吞作用内化到细胞体中。视紫红质在光感受器细胞质内以不溶性聚集体积聚。这定义了一种新的细胞凋亡信号通路，该通路负责许多果蝇突变体的视网膜变性。有趣的是，在几种不同形式的常染色体显性视网膜色素变性中，观察到视紫红质和视紫红质抑制蛋白之间存在稳定的复合物。此外，许多神经元退行性疾病的特征是细胞内蛋白质复合物的积累，表明这可能是用于多种疾病的常见细胞凋亡机制。为了进一步表征这种新颖的细胞凋亡途径，将采用三种实验方法。 1）。我们将确定视紫红质抑制蛋白和 AP2 异四聚体之间的相互作用是否对视紫红质内吞作用至关重要。 2）。我们将研究视紫质和视紫红质的内体运输在细胞死亡激活中的作用。 3）。将进行遗传筛选以分离参与这种新型细胞凋亡信号传导途径的基因产物。涉及视紫红质/抑制蛋白复合物形成与细胞死亡机制耦合的基因产物将被鉴定和表征。