Elp1 function in Familial Dysautonomia

 描述(申请人提供)：家族性自主神经障碍(FD)是一种罕见的遗传性疾病，其特征是由人类Elp1基因(IKBKAP)的高度保守的种系点突变引起的严重的进行性交感和感觉神经元丢失。Elp1是异源六聚体转录Elongator复合体的一个高度保守的亚基，但它如何在疾病脆弱的神经元中发挥作用还知之甚少。我们建议研究Elp1在交感神经元发育和神经支配中的作用。该项目的三个具体目标是：(1)确定Elp1在交感神经靶组织神经支配和维持成年交感神经支配动态平衡中的功能；(2)确定在神经细胞质中介导Elp1功能的信号通路和相互作用蛋白；(3)表征其在神经生长因子信号转导中的作用，这是它们正常生存所必需的 和靶组织神经支配。数以百万计的人类患有涉及交感神经元和感觉神经元的疾病，但几乎所有这些疾病都无法治愈，因为调节它们生长和分化的机制知之甚少。我们预计，这些专注于一种罕见的神经病变相关蛋白的研究将确定新的信号转导途径，这些信号转导途径对周围神经元的生存、分化和 神经动态平衡。此外，我们预计这些研究将阐明交感神经元中与疾病相关的基本信号通路，这些信号通路可能被用来治疗发育和退行性周围神经疾病。

 DESCRIPTION (provided by applicant): Familial Dysautonomia (FD) is a rare genetic disease characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human Elp1 (IKBKAP) gene. Elp1 is a highly conserved subunit of the hetero-hexameric transcriptional Elongator complex, but how it functions in disease vulnerable neurons is very poorly understood. We propose to study the role of Elp1 in sympathetic neuron development and innervation. The project is outlined in three specific aims to: (1) characterize Elp1 function in sympathetic neuron target tissue innervation and in maintaining adult sympathetic neuron innervation homeostasis, (2) to identify signaling pathways and interacting proteins that mediate its function in the neuron cytoplasm and (3) to characterize its role in nerve growth factor signaling which is essential for their normal survival and target tissue innervation. Millions of humans are afflicted with diseases involving sympathetic and sensory neurons, yet almost all of them are untreatable because the mechanisms regulating their growth and differentiation are very poorly understood. We anticipate that these studies focused on a rare neuropathy-associated protein will identify new signal transduction pathways that are essential for peripheral neuron survival, differentiation and innervation homeostasis. Moreover, we anticipate that these studies will elucidate essential disease-relevant signaling pathways in sympathetic neurons that may be exploited to treat developmental and degenerative peripheral neuropathies.