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、抑郁症、癫痫、中风和神经退行性疾病。在理解胚胎和成人神经发生损伤如何影响这些疾病方面存在根本的差距。NIBP是核因子κ B （NFkB）信号传导的一种新型调节剂，与智力低下、自闭症、听力损失等神经发育障碍有关。目前迫切需要了解NIBP/NFkB信号在神经发育障碍中的潜在因果关系和机制。长期目标是了解如何操纵NIBP/NFkB信号以达到预防和治疗目的。本研究的目的是明确NIBP/NFkB信号在胚胎和成人神经发生中的作用和机制。核心假说认为，在神经发生过程中，NFkB信号在NIBP等相关蛋白的控制下，诱导一组基因关闭干性，触发分化，维持细胞存活，指导神经元细胞的命运承诺。该假设是在前人研究和申请人自己的初步数据的基础上提出的，表明：(1)NIBP/NFkB信号在调节早期神经分化中起关键作用；(2)斑马鱼NIBP的功能性敲低导致大脑发育严重缺陷；(3)在小鼠和培养的神经干/祖细胞（NSCs/ npc）中，常规和条件crep介导的NIBP敲除会减弱神经元的分化。提出这项研究的基本原理是识别

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.