Development and characterization of NIBP conditional knockout mice

NIBP条件敲除小鼠的发育和表征

• 批准号: 8317553
• 负责人: Wenhui Hu
• 金额: $ 19.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317553
• 关键词: Address; Adult; Animal Model; Apoptosis; Autistic Disorder; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Basic Science; Behavior; Binding Proteins; Biological Assay; Biological Models; Brain; Breeding; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Chronic Disease; Clinical; Clinical Data; Cognitive; Complex; Crossbreeding; Defect; Development; Developmental Delay Disorders; Disease; Embryo; Engineering; Face; Generations; Genes; Genetic Recombination; Genome; Growth Cones; Human; Immunity; In Vitro; Inflammation Mediators; Inflammatory; Institutes; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Malignant Bone Neoplasm; Malignant Neoplasms; Mental Retardation; Modeling; Mus; Mutation; Neonatal; Nerve Growth Factors; Nervous system structure; Neurodegenerative Disorders; Neuronal Differentiation; Neuronal Plasticity; Neurons; Outcome; Pathogenesis; Phenotype; Phosphotransferases; Pilot Projects; Play; Prevalence; Protein Family; Proteins; Research; Retinal Dystrophy; Rosa; Science; Signal Transduction; Signaling Protein; Single Nucleotide Polymorphism; Source; Staging; Stem cells; Stroke; Syndrome; System; Tamoxifen; Techniques; Testing; Time; Transgenic Mice; United States National Institutes of Health; Zebrafish; adult neurogenesis; bone loss; cell growth; cell type; cytokine; genome-wide; hearing impairment; human disease; in vivo; innovation; insight; interest; knockout gene; member; mental development; mouse model; nerve stem cell; nestin protein; neurobehavioral disorder; neurogenesis; novel; particle; postnatal; protein transport; relating to nervous system; stem; trafficking

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.

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。该提案的长期目标是建立一种新型小鼠模型系统，以研究由靶向新型蛋白NIBP（NIK和IKK 2结合蛋白）的缺失或破坏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，包括常染色体隐性遗传性精神发育迟滞，自闭症，听力损失，中风等的重要性，这些临床研究结果突出了NIBP在神经发生，智力发育和认知行为的重要性。然而，潜在的因果关系和机制仍然未知。 NIBP增强了尼古丁诱导的NF：B活化，NF：B是炎症、免疫和神经可塑性的主要介质，是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、骨丢失和癌症的关键参与者。NIBP也是运输蛋白颗粒（TRAPP）复合物II的关键成员，这意味着它在调节细胞运输中的重要性。NIBP在广泛的科学领域中的广泛功能促使我们产生NIBP条件敲除小鼠。在使用cre-loxP条件基因敲除和Red重组工程技术的初步研究中，我们产生了floxed NIBP转基因小鼠。在本提案的目标1中，我们将通过将floxed NIBP小鼠与通用和诱导型cre小鼠杂交，然后在胚胎、出生后（P5-P10）、年轻（1-2个月）和成年（6-8个月）小鼠中进行他莫昔芬诱导，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敲除对胚胎和成体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型Cre小鼠（Neurog 1-Cre/ERT）产生不同发育阶段的神经元特异性NIBP敲除小鼠。这些小鼠将是理想的模型，以测试一个新的假设，NIBP优先指导神经元谱系的发展和维持成熟的神经元功能。将研究神经干/祖细胞中NIBP和神经生成素1之间的相互作用。 这些条件性NIBP敲除小鼠的表型分析将鉴定潜在的疾病相关综合征。项目说明：拟议的研究结果将最终解决NIBP在多个系统和人类疾病，如精神发育迟滞的功能和机制。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流行的慢性疾病中NF：B信号和蛋白质运输的了解。这些小鼠将适用于多个NIH研究所/中心的研究兴趣。