IKBKAP function in SNS development

SNS开发中的IKBKAP功能

基本信息

批准号：
8128471
负责人：
WARREN G TOURTELLOTTE
金额：
$ 18.3万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128471
关键词：
Adult Affect Afferent Neurons Age Animal Model Autonomic Nervous System Part Autonomic nervous system Axon Behavioral Cancerous Cells Cessation of life Childhood Clinical Complex Defect Development Differentiation and Growth Disease Dysautonomias Embryo Escherichia coli Exons Familial Dysautonomia Future Gene Expression Regulation Genes Genetic Hereditary Disease Hereditary Sensory Neuropathy Homeostasis Human In Vitro Introns Knock-out Knockout Mice Laboratories Laboratory Research Lead Lentivirus Vector Maintenance Malignant - descriptor Mediating Methods Mission Modeling Mus Mutagenesis Mutation Nerve Degeneration Nervous system structure Neurites Neurodegenerative Disorders Neurons Online Mendelian Inheritance In Man Organ Partner in relationship Pathogenesis Phenotype Physiological Point Mutation Process Proteins Quality of life RNA Polymerase II RNA Splicing Recombinants Regulator Genes Reporter Resources Role Sensory Signal Transduction Site Small Interfering RNA Source Staging Subfamily lentivirinae Sympathetic Nervous System Techniques Testing Tissues Transcript Transcriptional Regulation Transfection Transgenic Mice Transgenic Organisms Unconscious State Universities autonomic neuropathy base cell motility cell type design embryonic stem cell experience functional loss homologous recombination in vivo insight loss of function mRNA Stability migration mouse model neoplastic nerve supply nervous system development neuron development neuropathology premature protein function public health relevance recombinase research study response small hairpin RNA tool tumor vector

项目摘要

DESCRIPTION (provided by applicant): The sympathetic nervous system (SNS) is a division of the autonomic nervous system that has a major role in tissue and organ homeostasis. It is the target of a wide variety of congenital and neurodegenerative diseases, and the source of several types of malignant pediatric and adult tumors. Millions of humans are afflicted with diseases involving the SNS, yet we understand very little about the mechanisms regulating growth and differentiation of sympathetic neurons or the mechanisms mediating the establishment and maintenance of target organ innervation. Familial Dysautonomia (FD, Riley Day Syndrome, HSAN3) is a devastating genetic autosomal recessive disease involving the sympathetic and sensory nervous systems. In greater than 99.5% of cases, it is caused by a single highly conserved point mutation of the IKBKAP gene. IKBKAP encodes a protein (IKAP) with very poorly characterized function. Here, we propose to study the function of IKBKAP in sympathetic and sensory neurons most affected by FD using in vitro and in vivo methods. This exploratory/developmental proposal is outlined with 2 specific aims: (1) to study IKAP function in sympathetic neurons in vivo by generating a mouse model to conditionally ablate (knockout) IKBKAP and (2) to examine the role of IKAP in growth, differentiation and axon outgrowth of sympathetic and sensory neurons in vitro. We anticipate that these studies will generate new insights into how IKAP functions during development of sympathetic and sensory neurons. Moreover, the conditional IKBKAP knockout mouse will provide a valuable tool for further studies aimed at elucidating prevailing gene regulatory networks controlled by IKAP that are involved in sympathetic and sensory nervous system development and maintenance in humans. PUBLIC HEALTH RELEVANCE: The sympathetic nervous system (SNS) is critical for controlling many unconscious processes in the body and it is the target of a wide variety of developmental, degenerative and cancerous diseases. Familial Dysautonomia (FD) is a devastating genetic disease involving the sympathetic and sensory nervous systems and is caused by mutation of the IKBKAP gene. Very little is known about IKBKAP and its role in developing and adult sympathetic neurons. Here, we will generate an animal model that will make it possible to study in detail how mutation of IKBKAP leads to FD.

描述（由申请人提供）：交感神经系统（SNS）是自主神经系统的一个部分，在组织和器官稳态中发挥着重要作用。它是多种先天性和神经退行性疾病的靶标，也是多种儿童和成人恶性肿瘤的来源。数以百万计的人类患有涉及交感神经系统的疾病，但我们对调节交感神经元生长和分化的机制或介导靶器官神经支配的建立和维持的机制知之甚少。家族性自主神经功能障碍（FD、Riley Day Syndrome、HSAN3）是一种破坏性常染色体隐性遗传疾病，涉及交感神经和感觉神经系统。超过 99.5% 的病例是由 IKBKAP 基因的单个高度保守的点突变引起的。 IKBKAP 编码的蛋白质 (IKAP) 的功能特征非常少。在这里，我们建议使用体外和体内方法研究 IKBKAP 在受 FD 影响最严重的交感神经元和感觉神经元中的功能。这一探索性/开发性提案概述了 2 个具体目标：(1) 通过生成小鼠模型来有条件地消融（敲除）IKBKAP，研究体内交感神经元中的 IKAP 功能；(2) 检查 IKAP 在生长、分化中的作用以及体外交感神经元和感觉神经元的轴突生长。我们预计这些研究将对 IKAP 在交感神经元和感觉神经元发育过程中如何发挥作用产生新的见解。此外，条件性IKBKAP敲除小鼠将为进一步研究提供有价值的工具，旨在阐明由IKAP控制的、参与人类交感神经和感觉神经系统发育和维持的普遍基因调控网络。公共健康相关性：交感神经系统 (SNS) 对于控制体内许多无意识过程至关重要，并且是多种发育性疾病、退行性疾病和癌症疾病的目标。家族性自主神经功能障碍 (FD) 是一种涉及交感神经和感觉神经系统的破坏性遗传疾病，由 IKBKAP 基因突变引起。关于 IKBKAP 及其在发育中和成年交感神经元中的作用，人们知之甚少。在这里，我们将生成一个动物模型，使详细研究 IKBKAP 突变如何导致 FD 成为可能。