Reciprocal Signaling In Synaptogenesis

人类亚瑟综合征是导致聋盲的最常见原因，大约每17000名美国人中就有一人受到影响 以光感受器进行性丧失和先天性视网膜变性为特征 耳聋。尽管至少有12个不同的基因座与亚瑟综合征有关，我们知道其身份 在9个基因中，疾病的病因和潜在的机制仍然知之甚少。基于 对Usher综合征动物模型的研究，我们提出了一种新的视力丧失的解释； 光感受器的节段和随后的死亡是由于光感受器期间较早的初级缺陷所致 发展。我们假设Ush2a和Ush2c与其他结合在一起的Usher蛋白形成一个复合体 至Ushlc，以调节光感受器和二级神经元之间的相互信号。这一信号 是形成和维持正常突触所必需的。Usher介导的信号转导缺陷导致 突触功能障碍与细胞凋亡。为了检验这一假设，我们将1)了解Ush2a和Ush2c 信号调节突触的形成和维持以及2)Ush2a和Ush2c在哪里以及如何相互作用 与其他Usher蛋白结合。这些实验将有助于揭示细胞和生化机制 Usher综合征的基础，允许我们将Usher基因组装到一个遗传网络中，并阐明Usher 蛋白质的相互作用。我们还将使用基因筛查来识别亚瑟网络中的新基因和新的 已知的Usher基因突变。总之，这些分析将确定Usher的关键组件 基因网络，并提供了对亚瑟综合征的综合理解。

Human Usher syndrome, the most frequent cause of deaf blindness, affects about 1 in 17,000 Americans and is characterized by retinal degeneration due to progressive loss of photoreceptors and congenital deafness. Although at least 12 different loci have been linked to Usher syndrome and we know the identity of nine genes, etiology of the disease and underlying mechanisms are still poorly understood. Based on studies of animal models of Usher syndrome, we propose a new explanation for vision loss; damage to outer segments and subsequent death of photoreceptors is due to an earlier primary defect during photoreceptor development. We hypothesize that Ush2a and Ush2c act in a complex with other Usher proteins, all bound to Ushlc, to mediate reciprocal signaling between photoreceptors and second order neurons. This signaling is required for proper synapse formation and maintenance. Defects in Usher mediated signaling lead to synaptic dysfunction and apoptosis. To test this hypothesis we will 1) learn whether Ush2a and Ush2c signaling mediates synapse formation and maintenance and 2) where and how Ush2a and Ush2c interact with other Usher proteins. These experiments will help reveal the cellular and biochemical mechanisms that underlie Usher syndrome, allow us to assemble the Usher genes into a genetic network and elucidate Usher protein interactions. We will also use genetic screens to identify new genes in the Usher network and new mutations in known Usher genes. Together, these analyses will identify the critical components of the Usher gene network and provide an integrated understanding of Usher syndrome.