Lung specific TNF-R1 signaling in TRUSS null mice

TRUSS 无效小鼠的肺特异性 TNF-R1 信号传导

• 批准号: 7496933
• 负责人: David W. Riches
• 金额: $ 19.72万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496933
• 关键词: Acute Lung Injury; Adult; Apoptosis; Asthma; Bacterial Infections; Binding; Boxing; Breeding; Cells; Cloning; Constriction procedure; Development; Disease; ES Cell Line; Elements; Event; Exons; Generations; Genes; Goals; Grant; Host Defense; In Vitro; Inflammatory; Injury; Investigation; Joints; Knockout Mice; Laboratory Study; Link; Lung; Lung Inflammation; Lung diseases; MAPK8 gene; Mus; Muscle Contraction; Mutant Strains Mice; Natural Immunity; Nucleic Acid Regulatory Sequences; Organ; Phenotype; Physiological; Play; Pneumonia; Production; Proteins; Publishing; Pulmonary Edema; Pulmonary Fibrosis; Resources; Respiratory physiology; Rheumatoid Arthritis; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Silicosis; Site; Smooth Muscle Myocytes; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Receptor; Viral; Work; base; cytokine; homologous recombination; in vivo; insight; macrophage; novel; pathogen; pathogenic bacteria; promoter; protein function; recombinase; respiratory smooth muscle; response; tool; vector

DESCRIPTION (provided by applicant): Signaling by the TNF-a receptor TNF-R1 is necessary for the development of pulmonary inflammation and injury, and for innate host defense of the lung. Understanding the mechanisms involved in TNF-R1 signaling and function therefore holds the promise of therapeutic control of lung inflammation and injury. Recent studies from this laboratory have led to the discovery and cloning of TRUSS (TNF-R1 Ubiquitous Signaling and Scaffolding protein), a ubiquitous and previously unknown protein involved in TNF-R1-induced activation of NF-?B, JNK and apoptosis. Currently, nothing is known about the role of TRUSS in vivo though it is highly expressed in macrophages and in lung cells. In this exploratory/developmental R21 application, we propose developing adult conditional TRUSS-deficient mice to enable the in vivo role of TRUSS in lung inflammation, injury and host defense to be determined. We propose three specific aims. Based on current progress in the creation of TRUSS null mice, the goal of aim one is to complete the generation of mice that are heterozygous for the loxP-flanked truss exon 1 and putative regulatory region (truss+/flox). In aim two, we will intercross these mice with deleter-Cre or ROSA26 ERCre transgenic mice to create mice in which TRUSS has been constitutively- or inducibly-deleted in all cells and tissues by transgenic expression of Cre-recombinase. The goal of aim three is to conduct a preliminary characterization of the phenotype of these mice with regard to their ability to develop TNF-R1-dependent lung inflammation and injury and to eliminate bacterial infections. In addition to the proposed studies, these mice will be shared with other laboratories that are studying the role of TRUSS in silicosis and airway smooth muscle cell contraction and cytokine production. Thus, this proposal seeks to develop a new mutant mouse strain to serve as a resource for the investigation of TRUSS function in the lung and other organs. RELEVANCE: TNF-a plays a key role that in inflammatory disorders of the lung (e.g. acute lung injury, severe asthma) and joints (e.g. rheumatoid arthritis), and in host defense against pathogenic bacteria. The work in this application will provide new insights into how TNF-a, operating through a molecule called TRUSS, initiates and regulates these disorders. Understanding the role of TRUSS in TNF-a-induced response may provide a new target for treating these disorders.

描述（由申请人提供）：TNF-α受体TNF-R1的信号传导对于肺部炎症和损伤的发展以及肺的先天宿主防御是必需的。因此，了解TNF-R1信号传导和功能的机制有望对肺部炎症和损伤进行治疗控制。最近的研究，从这个实验室导致发现和克隆TRUSS（TNF-R1无处不在的信号和支架蛋白），一个无处不在的和以前未知的蛋白参与TNF-R1诱导的NF-κ B激活？B、JNK与细胞凋亡。目前，对TRUSS在体内的作用一无所知，尽管它在巨噬细胞和肺细胞中高度表达。在这种探索性/开发性R21应用中，我们建议开发成年条件性TRUSS缺陷小鼠，以确定TRUSS在肺部炎症，损伤和宿主防御中的体内作用。我们提出三个具体目标。基于目前在TRUSS缺失小鼠的创建中的进展，目标一的目标是完成对于loxP侧翼的truss外显子1和推定的调控区（truss+/flox）为杂合的小鼠的产生。在目标二中，我们将这些小鼠与deleter-Cre或ROSA 26 ERCre转基因小鼠杂交，以创建其中TRUSS已通过Cre重组酶的转基因表达在所有细胞和组织中组成性或诱导性缺失的小鼠。目标三的目标是对这些小鼠的表型进行初步表征，以确定其发展TNF-R1依赖性肺部炎症和损伤以及消除细菌感染的能力。除了拟议的研究外，这些小鼠还将与正在研究TRUSS在硅肺和气道平滑肌细胞收缩和细胞因子产生中的作用的其他实验室共享。因此，该提案旨在开发一种新的突变小鼠品系，作为研究肺和其他器官中TRUSS功能的资源。相关性：TNF-α在肺（例如急性肺损伤、严重哮喘）和关节（例如类风湿性关节炎）的炎性病症中以及在宿主防御病原菌中起关键作用。这项应用的工作将为TNF-a如何通过一种名为TRUSS的分子启动和调节这些疾病提供新的见解。了解TRUSS在TNF-α诱导的反应中的作用可能为治疗这些疾病提供新的靶点。