IKBKAP function in SNS development

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分支，在组织和器官稳态中起主要作用。它是多种先天性和神经退行性疾病的靶点，也是几种类型的恶性儿科和成人肿瘤的来源。数以百万计的人类患有涉及SNS的疾病，但我们对交感神经元的生长和分化的调节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综合征，HSAN 3）是一种破坏性的常染色体隐性遗传疾病，涉及交感神经和感觉神经系统。在超过99.5%的病例中，它是由IKBKAP基因的单一高度保守点突变引起的。IKBKAP编码的蛋白（IKAP）具有非常差的功能。在这里，我们建议研究的功能IKBKAP在交感神经元和感觉神经元的FD最受影响的使用在体外和体内的方法。该探索性/发展性提议概述了2个具体目标：（1）通过产生小鼠模型以条件性地消融（敲除）IKBKAP来研究体内交感神经元中的IKAP功能，以及（2）检查IKAP在体外交感神经元和感觉神经元的生长、分化和轴突生长中的作用。我们预计，这些研究将产生新的见解IKAP如何在交感神经元和感觉神经元的发展过程中的功能。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流行基因调控网络。 公共卫生相关性：交感神经系统（SNS）对于控制身体中的许多无意识过程是至关重要的，并且它是多种发育、退行性和癌症疾病的目标。家族性自主神经功能障碍（FD）是一种累及交感神经和感觉神经系统的遗传性疾病，由IKBKAP基因突变引起。关于IKBKAP及其在发育和成年交感神经元中的作用知之甚少。在这里，我们将生成一个动物模型，这将使详细研究IKBKAP突变如何导致FD成为可能。

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.