Elp1 function in Familial Dysautonomia

Elp1 在家族性自主神经功能障碍中的功能

基本信息

批准号：
9078576
负责人：
WARREN G TOURTELLOTTE
金额：
$ 36.03万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078576
关键词：
Address Adult Afferent Neurons Autonomic nervous system Axon Binding Biochemical Biological Assay Cells Complex Congenital neurologic anomalies Cytoplasm Cytoplasmic Tail Dendrites Development Differentiation and Growth Disease Dysautonomias Familial Dysautonomia Fibroblasts Functional disorder Gene Mutation Genes Genetic Transcription Hereditary Disease Hereditary Sensory Neuropathy Hereditary Sensory and Autonomic Neuropathies Homeostasis Human In Vitro Knockout Mice Leukocytes Maps Mediating Methods Molecular Molecular Genetics Motor Mus Nerve Growth Factors Neurites Neuroglia Neurons Neuropathy Pathogenesis Patients Peripheral Peripheral Nervous System Diseases Physiological Point Mutation Presynaptic Terminals Proteins Proteomics Role Sensory Signal Pathway Signal Transduction Signal Transduction Pathway Splice-Site Mutation Sympathetic Nervous System Techniques Testing Tissues Transcriptional Regulation autonomic neuropathy disease-causing mutation in vivo insight nerve supply nervous system development neuron development neuron loss novel public health relevance signal processing

项目摘要

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.

描述（由申请人提供）：家族性自主神经功能障碍（FD）是一种罕见的遗传性疾病，其特征是由人类Elp1（IKBKAP）基因的高度保守的种系点突变引起的严重的进行性交感神经和感觉神经元丧失，Elp1是高度保守的亚基。 Elp1 是异源六聚体转录延伸复合物的重要组成部分，但我们对它在疾病脆弱神经元中的作用知之甚少，我们建议研究 Elp1 在交感神经元发育和发育中的作用。该项目概述了三个具体目标：(1) 表征 Elp1 在交感神经元靶组织神经支配和维持成人交感神经元神经支配稳态中的功能，(2) 识别介导其在神经元中功能的信号通路和相互作用蛋白。细胞质和（3）表征其在神经生长因子信号传导中的作用，这对其正常生存至关重要数以百万计的人患有交感神经和感觉神经元疾病，但几乎所有这些疾病都是无法治疗的，因为我们对调节其生长和分化的机制知之甚少。蛋白质将识别新的信号转导途径，这些途径对于周围神经元的生存、分化和此外，我们预计这些研究将阐明交感神经元中与疾病相关的重要信号通路，可用于治疗发育性和退行性周围神经病。