Lung specific TNF-R1 signaling in TRUSS null mice

描述（由申请人提供）：TNF-a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要的。因此，了解TNF-R1信号传导和功能的机制有助于治疗控制肺部炎症和损伤。该实验室最近的研究导致了TRUSS （TNF-R1泛在信号和支架蛋白）的发现和克隆，这是一种普遍存在且以前未知的蛋白，参与TNF-R1诱导的NF-？B， JNK和细胞凋亡。虽然TRUSS在巨噬细胞和肺细胞中高表达，但目前对其在体内的作用尚不清楚。在这个探索性/发展性R21应用中，我们建议培养成年条件TRUSS缺陷小鼠，以确定TRUSS在肺炎症、损伤和宿主防御中的体内作用。我们提出三个具体目标。基于目前构建TRUSS缺失小鼠的进展，目的一是完成loxp侧翼TRUSS外显子1和假定的调控区（TRUSS +/flox）杂合小鼠的生成。在目标二中，我们将这些小鼠与deleter-Cre或ROSA26 ERCre转基因小鼠交叉，通过转基因cre -重组酶的表达，使TRUSS在所有细胞和组织中被组成性或诱导性地删除。目的三是对这些小鼠的表型进行初步表征，以确定它们发生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，这些小鼠将与其他正在研究TRUSS在矽肺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，本提案寻求开发一种新的突变小鼠品系，作为研究TRUSS在肺和其他器官中的功能的资源。相关性：TNF-a在肺部炎症性疾病（如急性肺损伤、严重哮喘）和关节（如类风湿关节炎）以及宿主对致病菌的防御中发挥关键作用。这项应用将为研究TNF-a如何通过一种叫做TRUSS的分子启动和调节这些疾病提供新的见解。了解TRUSS在tnf -a诱导反应中的作用可能为治疗这些疾病提供新的靶点。

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.