IKBKAP function in SNS development

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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.