Role and mechanism of NIBP/NFkB signaling in neurogenesis

描述(申请人提供)：神经发生在许多神经疾病的发病机制中起重要作用，包括神经发育缺陷、抑郁、癫痫、中风和神经退行性疾病。在理解胚胎和成人神经发生障碍如何影响这些疾病方面，存在着根本的差距。NIBP是一种新的核转录因子kappaB(NFkB)信号调节因子，与智力低下、自闭症、听力损失等神经发育障碍密切相关。长期目标是了解NIBP/NFkB信号如何被用于预防和治疗目的。这一建议的目的是明确NIBP/NFkB信号在胚胎和成人神经发生中的作用和机制。中心假说是，NFkB信号由NIBP和其他相关蛋白控制，诱导一系列基因关闭茎并触发分化，维持细胞存活，并在神经发生过程中引导神经细胞命运承诺。这一假说是基于先前的研究和申请人自己的初步数据提出的，这些数据表明：(1)NIBP/NFkB信号在调节早期神经分化中发挥关键作用；(2)在斑马鱼中，NIBP的功能被敲除会导致严重的脑发育缺陷；(3)在小鼠和培养的神经干细胞/祖细胞(NSCs/NPC)中，传统的和有条件的cre介导的NIBP基因敲除会抑制神经元的分化。这项拟议研究的基本原理是 对NIBP在神经发生不同阶段的作用的研究将有助于了解胚胎神经组织中神经发育的分子和细胞基础以及成人大脑中的神经维持。这一假设将通过追求3个具体目标来检验。在目标1中，将详细描述NIBP/NFkB信号在小鼠胚胎和成年神经发生中的作用。在目标2中，将阐明NIBP/NFkB信号在调节斑马鱼胚胎神经诱导和神经元谱系分化中的作用。在目标3中，将通过阐明NIBP如何调节NSCs/NPC中的NFkB信号并确定依赖于NIBP/NFkB的靶基因的激活或抑制对小鼠NSCs/NPC和斑马鱼胚胎中NSC的干性和早期分化的影响来探讨NIBP在神经发生中作用的分子机制。这项拟议的工作有望获得NIBP/NFkB信号在早期神经发生和神经元谱系特异性中的详细功能，以及控制和维持早期神经分化的特定基因。这些结果也能够为神经发育障碍、神经退行性疾病的发病机制以及神经损伤后的病理/生理反应提供更广泛的全面观点。这些结果有望对神经发生领域产生重要的积极影响，并为神经发育障碍的治疗提供指导。

DESCRIPTION (provided by applicant): Neurogenesis plays an important role in the pathogenesis of many neural diseases including neurodevelopmental defects, depression, epilepsy, stroke and neurodegenerative diseases. There is a fundamental gap in understanding how impairment of both embryonic and adult neurogenesis influences such diseases. NIBP is a novel regulator of the signaling for nuclear factor kappa B (NFkB) and implicated in neural developmental disorders such as mental retardation, autism, hearing loss, etc. There is an urgent need for understanding the underlying cause-effects and mechanisms of NIBP/NFkB signaling in neurodevelopmental disorders. The long-term goal is to understand how NIBP/NFkB signaling can be manipulated for preventive and therapeutic purposes. The objective of this particular proposal is to define the role and mechanisms of NIBP/NFkB signaling in embryonic and adult neurogenesis. The central hypothesis is that NFkB signaling, controlled by NIBP and other related proteins, induces a set of genes to shut down the stemness and trigger the differentiation, maintains the cellular survival and guides neuronal cell fate commitment during neurogenesis. The hypothesis has been formulated on the basis of previous studies and the applicants' own preliminary data showing that (1) NIBP/NFkB signaling plays key roles in modulating early neural differentiation; (2) Functional knockdown of NIBP in zebrafish leads to severe defects of brain development; (3) Conventional and conditional cre-mediated NIBP knockout in mice and cultured neural stem/progenitor cells (NSCs/NPCs) attenuates neuronal differentiation. The rationale for the proposed research is that identification of NIBP action at various stages of neurogenesis will contribute fundamental knowledge about the molecular and cellular bases of neurodevelopment in embryonic neural tissues and neural-maintenance in adult brains. This hypothesis will be tested by pursuing 3 specific aims. In aim 1, the detailed roles of NIBP/NFkB signaling in mouse embryonic and adult neurogenesis will be delineated. In aim 2, the role of NIBP/NFkB signaling in regulating neural induction and neuronal lineage differentiation in zebrafish embryos will be elucidated. In aim 3, the molecular mechanisms for NIBP actions in neurogenesis will be explored by elucidating how NIBP regulates NFkB signaling in NSCs/NPCs and determining the extent by which activation or inhibition of NIBP/NFkB-dependent target genes influence NSC stemness and early differentiation in mouse NSCs/NPCs and zebrafish embryos. The proposed work is expected to obtain detailed functions of NIBP/NFkB signaling in early neurogenesis and neuronal lineage specificity, as well as specific genes to control and maintain early neural differentiation. The results are also able to provide broaden apprehensive views of the pathogenesis of neurodevelopmental disorders, neurodegenerative diseases, and pathological/physiological responses after neural injuries. Such results are expected to produce an important positive impact on the field of neurogenesis and shed light on therapeutics for neurodevelopmental disorders.