Reciprocal Signaling In Synaptogenesis

人类Usher综合征是导致聋盲的最常见原因，每17，000名美国人中就有1人受到影响。 其特征在于由于光感受器的进行性丧失和先天性视网膜变性， 耳聋尽管至少有12个不同的基因位点与Usher综合征有关， 在九个基因中，疾病的病因和潜在机制仍然知之甚少。基于 通过对Usher综合征动物模型的研究，我们提出了一种新的解释，即视力丧失; 节和随后的光感受器死亡是由于早期的初级缺陷， 发展我们假设Ush 2a和Ush 2c与其他Usher蛋白结合在一起， 到Ushlc，介导光感受器和二级神经元之间的相互信号传导。该信令 是突触形成和维持所必需的Usher介导的信号传导缺陷导致 突触功能障碍和细胞凋亡。为了验证这一假设，我们将1）了解Ush 2a和Ush 2c是否 信号传导介导突触的形成和维持; 2）Ush 2a和Ush 2c在何处以及如何相互作用 其他Usher蛋白质。这些实验将有助于揭示细胞和生化机制， Usher综合征的基础，使我们能够将Usher基因组装成一个遗传网络， 蛋白质相互作用我们还将使用基因筛选来识别Usher网络中的新基因， 已知Usher基因的突变总之，这些分析将确定Usher的关键组件 基因网络，并提供Usher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.