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.
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. ? ? ?
| Terry Powers, Jennifer L; Mace, Kimberly E; Parfrey, Helen et al. (2010) TNF receptor-1 (TNF-R1) ubiquitous scaffolding and signaling protein interacts with TNF-R1 and TRAF2 via an N-terminal docking interface. Biochemistry 49:7821-9 |
| Mace, Kimberly E; Lussier, Marc P; Boulay, Guylain et al. (2010) TRUSS, TNF-R1, and TRPC ion channels synergistically reverse endoplasmic reticulum Ca2+ storage reduction in response to m1 muscarinic acetylcholine receptor signaling. J Cell Physiol 225:444-53 |
