Role and mechanism of NIBP/NFkB signaling in neurogenesis

NIBP/NFkB信号在神经发生中的作用和机制

• 批准号: 8722629
• 负责人: Wenhui Hu
• 金额: $ 20万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722629
• 关键词: Adult; Attenuated; Autistic Disorder; Binding Proteins; Biological Assay; Brain; Brain Diseases; Cells; Child; Clinical; Cognitive; Complex; Data; Defect; Development; Developmental Delay Disorders; Disease; Down Syndrome; Embryo; Environmental Risk Factor; Epilepsy; Exons; Face; Fragile X Syndrome; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genome; Goals; Homo; Human; I Kappa B-Alpha; Immunity; Impairment; Inflammation; Knock-out; Knockout Mice; Knowledge; LacZ Genes; Life; Light; Link; Maintenance; Mediating; Mental Depression; Mental Retardation; Mental disorders; Mission; Molecular; Mus; Mutation; NF-kappa B; Neuraxis; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Pathogenesis; Phosphotransferases; Physiological; Play; Prevalence; Preventive; Proteins; Public Health; Reporter; Research; Retinal Dystrophy; Rett Syndrome; Role; Schizophrenia; Signal Transduction; Single Nucleotide Polymorphism; Specificity; Staging; Stem cells; Stroke; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Work; Zebrafish; adult neurogenesis; autism spectrum disorder; base; cytokine; developmental disease; disability; disturbance in affect; gene therapy; genome-wide; hearing impairment; mental development; nerve injury; neurodevelopment; neurogenesis; novel; public health relevance; relating to nervous system; response; stem; stemness; trafficking

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.

描述（由申请人提供）：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的损伤如何影响这些疾病方面存在根本性的差距。NIBP是一种新型的核因子κ B（NFk B）信号转导调节因子，与神经发育障碍如智力低下、自闭症、听力损失等密切相关，因此迫切需要了解NIBP/NFk B信号转导在神经发育障碍中的作用机制。长期目标是了解NIBP/NFkB信号传导如何被操纵用于预防和治疗目的。本研究的目的是明确NIBP/NFkB信号在胚胎和成体神经发生中的作用和机制。核心假设是NIBP和其他相关蛋白控制的NFkB信号传导诱导一组基因关闭干细胞性并触发分化，维持细胞存活并指导神经发生期间的神经元细胞命运定型。该假设是基于先前的研究和申请人自己的初步数据而提出的，这些数据表明：（1）NIBP/NFkB信号传导在调节早期神经分化中起关键作用;（2）斑马鱼中NIBP的功能性敲低导致脑发育的严重缺陷;（3）常规和条件性cre介导的小鼠和培养的神经干/祖细胞（NSC/NPCs）中的NIBP敲除减弱神经元分化。拟议研究的基本原理是， NIBP在神经发生的各个阶段的作用将有助于对胚胎神经组织中神经发育和成人大脑中神经维持的分子和细胞基础的基础知识。这一假设将通过追求3个具体目标来检验。在目的1中，NIBP/NFkB信号转导在小鼠胚胎和成年神经发生中的详细作用将被描述。目的2：阐明NIBP/NFkB信号在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，NIBP在神经发生中的作用的分子机制将通过阐明NIBP如何调节NSC/NPC中的NFkB信号传导以及确定NIBP/NFkB依赖性靶基因的激活或抑制影响小鼠NSC/NPC和斑马鱼胚胎中的NSC干性和早期分化的程度来探索。该研究有望获得NIBP/NFkB信号在早期神经发生中的详细功能和神经元谱系特异性，以及控制和维持早期神经分化的特异性基因。这些结果也能够为神经发育障碍、神经退行性疾病和神经损伤后的病理/生理反应的发病机制提供更广泛的理解。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线索。