IKBKAP function in SNS development

描述(申请人提供)：交感神经系统(SNS)是自主神经系统的一个分支，在组织和器官的动态平衡中起着重要作用。它是各种先天性和神经退行性疾病的靶点，也是几种类型的儿童和成人恶性肿瘤的来源。数以百万计的人类被涉及SNS的疾病所困扰，但我们对交感神经元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。家族性自主神经异常(FD，Riley Day综合征，HSAN3)是一种侵袭性常染色体隐性遗传病，累及交感神经系统和感觉神经系统。在99.5%以上的病例中，它是由IKBKAP基因的一个高度保守的点突变引起的。IKBKAP编码一种功能很差的蛋白质(IKAP)。在此，我们拟通过体外和体内方法研究受FD影响最大的交感和感觉神经元中IKBKAP的功能。这一探索性/发展计划有两个具体目的：(1)通过建立有条件地去除(敲除)IKBKAP的小鼠模型，研究IKAP在体内交感神经元中的功能；(2)研究IKAP在交感神经元和感觉神经元生长、分化和轴突生长中的作用。我们预计，这些研究将对IKAP在交感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，有条件的IKBKAP基因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和感觉神经系统发育和维护的普遍基因调控网络。 公共卫生相关性：交感神经系统(SNS)是控制体内许多无意识过程的关键，它是各种发育、退行性和癌症疾病的靶标。家族性自主神经异常(FD)是一种涉及交感神经系统和感觉神经系统的破坏性遗传病，由IKBKAP基因突变引起。人们对IKBKAP及其在发育和成人交感神经元中的作用知之甚少。在这里，我们将建立一个动物模型，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.