Development and characterization of NIBP conditional knockout mice

描述（由申请人提供）：分子工程动物模型的产生为人类疾病的发病机制提供了宝贵的见解。本课题的长期目标是建立一种新的小鼠模型系统，以研究由于靶蛋白NIBP （NIK和ikk2结合蛋白）的丢失或破坏而引起的潜在人类疾病的发病机制和机制。有限的新的临床数据已经确定了NIBP在一些人类疾病中的重要性，包括常染色体隐性智力低下、自闭症、听力损失、中风等。这些临床发现强调了NIBP在神经发生、智力发育和认知行为中的重要性。然而，潜在的因果关系和机制仍然未知。NIBP增强细胞因子诱导的NF:B的激活，NF:B是炎症、免疫和神经可塑性的主要介质，在多种发育缺陷和各种慢性疾病（如神经退行性疾病、自身免疫性疾病、骨质流失和癌症）中起关键作用。NIBP也是运输蛋白颗粒（TRAPP）复合体II的关键成员，暗示其在调节细胞运输中的重要性。NIBP在广泛科学领域的广泛功能促使我们产生NIBP条件敲除小鼠。在一项使用cre-loxP条件基因敲除和Red重组技术的初步研究中，我们生产了floxed NIBP转基因小鼠。在本研究的目标1中，我们将在胚胎、产后（P5-P10）、幼龄（1-2个月）和成年（6-8个月）小鼠中，通过与通用型和可诱导型cre小鼠杂交，产生不同发育阶段的通用NIBP敲除小鼠。这些小鼠将帮助我们识别潜在的疾病相关表型，并为进一步研究提供广泛的主题。NIBP敲除对胚胎和成人神经发生的影响将被确定。在目标2中，我们将使用神经元特异性诱导Cre小鼠（Neurog1-Cre/ERT）在不同发育阶段产生神经元特异性NIBP敲除小鼠。这些小鼠将是测试NIBP优先引导神经元谱系发育和维持成熟神经元功能的新假设的理想模型。NIBP和Neurogenin1在神经干/祖细胞中的相互作用将被研究。对这些条件NIBP敲除小鼠的表型分析将确定潜在的疾病相关综合征。项目描述：拟议研究的结果将最终解决NIBP在多个系统和人类疾病（如智力迟钝）中的功能和机制。该项目的成功完成将为人类疾病或综合征提供新的线索，并大大增加我们对最常见慢性疾病中NF:B信号传导和蛋白质转运的认识。这些小鼠将适用于多个NIH研究所/中心的研究兴趣。

DESCRIPTION (provided by applicant): The generation of molecularly engineered animal models has provided invaluable insight into the pathogenesis of human diseases. The long-term objective of this proposal is to establish a novel mouse model system to study the pathogenesis and mechanism of potential human diseases caused by the loss or disruption of the target novel protein NIBP (NIK and IKK2-binding protein). Limited new clinical data have identified the importance of NIBP in a few human diseases including autosomal recessive mental retardation, autism, hearing loss, stroke, etc. These clinical findings highlight the importance of NIBP in neurogenesis, mental development, and cognitive behavior. However, the underlying cause-effect relationships and mechanisms remain unknown. NIBP enhances cytokine-induced activation of NF:B, a major mediator for inflammation, immunity and neural plasticity, and a key player in multiple developmental defects and various chronic diseases such as neurodegenerative diseases, autoimmune, bone loss and cancer. NIBP is also a key member of trafficking protein particle (TRAPP) complex II, implying its importance in regulating cellular trafficking. The extensive functions of NIBP in the broad science fields prompted us to generate NIBP conditional knockout mice. In a pilot study using the cre-loxP conditional gene knockout and Red recombineering techniques, we produced floxed NIBP transgenic mice. In aim 1 of this proposal, we will generate universal NIBP knockout mice at different stages of development by crossbreeding floxed NIBP mice with universal and inducible cre mice followed by Tamoxifen induction in embryonic, postnatal (P5-P10), young (1-2 months) and adult (6-8 months) mice. These mice will help us to identify potential disease-related phenotypes and provide extensive topics for further studies. The effect of NIBP knockout on embryonic and adult neurogenesis will be identified. In aim 2, we will generate neuron-specific NIBP knockout mice at different developmental stages by using neuron-specific inducible Cre mice (Neurog1-Cre/ERT). These mice will be ideal models to test a novel hypothesis that NIBP preferentially guides neuronal lineage development and maintains mature neuronal functions. Mutual interaction between NIBP and Neurogenin1 in neural stem/progenitor cells will be investigated. Phenotypic analysis of these conditional NIBP knockout mice will identify potential disease-related syndromes. Project narrative: The outcome of the proposed studies will conclusively address the functions and mechanisms of NIBP in multiple systems and human diseases such as mental retardation. The successful accomplishment of this project will provide new clues for human diseases or syndromes and substantially increase our knowledge of NF:B signaling and protein trafficking in the most prevalent chronic diseases. These mice will be applicable to the research interests of multiple NIH institutes/centers. PUBLIC HEALTH RELEVANCE: The outcome of the proposed studies will conclusively address the functions and mechanisms of NIBP in multiple systems and human diseases such as mental retardation. The successful accomplishment of this project will provide new clues for human diseases or syndromes and substantially increase our knowledge of NF:B signaling and protein trafficking in the most prevalent chronic diseases. These mice will be applicable to the research interests of multiple NIH institutes/centers.