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-A受体TNF-R1的信号对于发展肺部炎症和损伤是必要的，对于肺的先天宿主防御。因此，了解TNF-R1信号传导和功能所涉及的机制具有治疗控制肺部炎症和损伤的希望。该实验室的最新研究导致了桁架（TNF-R1无处不在信号传导和脚手架蛋白）的发现和克隆，这是一种无处不在且以前未知的蛋白，参与TNF-R1诱导的NF-？B？b，JNK和凋亡。目前，尽管在巨噬细胞和肺部细胞中高度表达了桁架在体内的作用，但尚不了解。在此探索性/发育R21应用中，我们建议开发成年有条件的桁架缺陷小鼠，以使桁架在肺部炎症，损伤和宿主防御中的体内作用得以确定。我们提出了三个具体目标。基于目前创建桁架无效小鼠的进展，目标一个目标是完成对Loxp flank的桁架外显子1和推定的调节区域（Truss+/Flox）的杂合子的产生。在目标二中，我们将这些小鼠与deleter-cre或rosa26 ercre转基因小鼠互变，以创建小鼠，其中桁架已通过CRE - 成分酶的转基因表达在所有细胞和组织中被组成或诱导地删除。目标三的目的是对这些小鼠的表型进行初步表征，以发展其发展TNF-R1依赖性肺部炎症和损伤并消除细菌感染的能力。除了提出的研究外，这些小鼠还将与其他正在研究桁架在硅氧病和气道平滑肌细胞收缩和细胞因子产生中的作用的实验室共享。因此，该提案试图开发一种新的突变小鼠菌株，以作为研究肺部和其他器官中桁架功能的资源。相关性：TNF-A在肺部炎症性疾病中（例如急性肺损伤，严重哮喘）和关节（例如类风湿关节炎）以及宿主防御致病细菌的关键作用。本应用程序中的工作将提供有关TNF-A通过称为桁架的分子操作的新见解，启动并调节这些疾病。了解桁架在TNF-A诱导的反应中的作用可能为治疗这些疾病提供一个新的靶标。