Initial functional characterization of TRUSS-deficient mice

TRUSS 缺陷小鼠的初步功能表征

基本信息

批准号：
8511974
负责人：
David W. Riches
金额：
$ 23.97万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511974
关键词：
Acute Acute Hepatitis Acute Liver Failure Address Affect Alleles Alzheimer&apos s Disease Apoptosis Apoptotic Biological Models Boxing Cartoons Caspase Cell Lineage Cells Clinical Cloning Communities Complex Development Disease Endothelial Cells Exhibits Flowers Gene Expression Genes Genetic Recombination Goals Hand Hepatitis Hepatocyte In Vitro Inflammation Inflammatory Injury Laboratories Late Onset Alzheimer Disease Leucine Zippers MAPK8 gene Malignant neoplasm of lung Mediating Mitochondria Modeling Mus Muscle Contraction Names Natural Immunity Outcome Pathway interactions Pattern Phenotype Protein Deficiency Proteins Publishing Reporting Research Personnel Resolution Rheumatoid Arthritis Right-On Role Scaffolding Protein Sepsis Side Signal Transduction Signaling Molecule Signaling Protein Specific qualifier value TNF gene TRAF2 gene Testing Tissues Tumor Necrosis Factor Receptor Work base cell type in vivo in vivo Model insight liver injury malignant breast neoplasm overexpression protein function public health relevance respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): Signaling by the TNF-¿ receptor, TNF-R1, is necessary for the development of inflammation, tissue injury and innate immunity. Recent studies from our laboratory have led to the discovery and characterization of TRUSS (TNF-R1 Ubiquitous Signaling and Scaffolding protein), a ubiquitous and previously unknown protein that serves as a rheostat to augment TNF-R1-induced activation of NF-?B, JNK and apoptosis. To allow assessment of the in vivo function of TRUSS in TNF-R1 signaling we have created mice bearing floxed truss alleles to allow conditional TRUSS deletion. In preliminary studies, we have shown that these mice undergo Cre-mediated recombination at the truss locus resulting in TRUSS deficiency. Our preliminary studies also indicate that TRUSS-/- mice are protected from hepatocyte apoptosis and acute hepatic failure induced by TNF- R1 signaling. Additional studies are now necessary to explore the phenotype of these recently created and validated mice. The goals of this exploratory/developmental R21 application are to: (i) evaluate the consequences of conditional TRUSS deficiency in hepatocytes and endothelial cells on TNF-R1-induced hepatocyte apoptosis and acute hepatitis and (ii) test the hypothesis that TRUSS augments TNF-R1-induced apoptosis through its ability to promote sustained JNK activation. These goals will be addressed by two specific aims. Using global TRUSS-deficient mice, hepatocyte-specific TRUSS deficient mice and endothelial cell-specific TRUSS deficient mice, specific aim 1 will test the hypothesis that hepatocyte apoptosis and acute fatal hepatitis are dependent on TRUSS. Specific aim 2 will test the hypothesis that the requirement for TRUSS in TNF-R1-induced hepatocyte apoptosis is to promote sustained JNK activation, which in turn activates caspases via the mitochondrial pathway. To our knowledge, the floxed truss mice described in this proposal are unique to our lab. The proposed studies will provide new insights into TRUSS function in vivo and will form the basis of a new R01 application. Recent studies by others have also implicated TRUSS in Alzheimer's disease and breast and lung cancer. Thus, in addition to the goals outlined above, our goal is to make these mice available to others investigators whose work focuses on this understudied gene.

描述（由应用提供）：TNF-€受体TNF-R1的信号对于感染，组织损伤和先天免疫学是必需的。我们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）的发现和表征，这是一种无处不在且以前未知的蛋白质，可作为变阻器，以增强TNF-R1诱导的NF-？B，JNK，JNK和凋亡。为了评估桁架在TNF-R1信号传导中的体内功能，我们创建了带有Floxed桁架等位基因的小鼠以允许有条件的桁架缺失。在初步研究中，我们表明这些小鼠在桁架基因座处经历了CRE介导的重组，从而导致桁架缺乏。我们的初步研究还表明，桁架 - / - 小鼠受到TNF-R1信号传导引起的肝细胞凋亡和急性肝衰竭的保护。现在需要进行其他研究来探索这些最近创建和验证的小鼠的表型。此探索性/发育R21应用的目标是：（i）评估TNF-R1诱导的肝细胞凋亡以及急性肝炎的条件桁架缺乏症的后果，并（II）测试TNF-R1诱导的popoptosis的假设，以促进TNF-R1的假设，以促进popoptopsis的促进。这些目标将由两个具体目标解决。使用全球桁架缺陷小鼠，肝细胞特异性的桁架特异性桁架特异性小鼠和内皮细胞特异性的桁架缺陷小鼠，特定的目标1将检验以下假设：肝细胞凋亡和急性致命肝炎依赖于桁架。特定的目标2将检验以下假设：TNF-R1诱导的肝细胞凋亡中桁架的需求是促进持续的JNK激活，进而通过线粒体途径激活caspases。据我们所知，本提案中描述的floxed桁架小鼠是我们实验室独有的。拟议的研究将提供对体内桁架功能的新见解，并将构成新的R01应用程序的基础。其他人最近的研究也实施了阿尔茨海默氏病，乳腺癌和肺癌的桁架。除了上面概述的目标外，我们的目标是使这些老鼠可用于其他人。研究人员的工作重点是这种理解的基因。