Initial functional characterization of TRUSS-deficient mice

TRUSS 缺陷小鼠的初步功能表征

• 批准号: 8649023
• 负责人: David W. Riches
• 金额: $ 20.01万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649023
• 关键词: Acute; Acute Hepatitis; Acute Liver Failure; Address; Affect; Alleles; Alzheimer' 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; Play; 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

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(申请人提供)：通过肿瘤坏死因子受体，肿瘤坏死因子-R1的信号，是发展炎症，组织损伤和先天免疫所必需的。最近我们实验室的研究发现并鉴定了Truss(肿瘤坏死因子-1无处不在的信号和支架蛋白)，这是一种普遍存在的未知蛋白质，可以作为变阻器来增强肿瘤坏死因子-1诱导的核因子-β、JNK和细胞凋亡。为了能够评估Truss在肿瘤坏死因子-R1信号中的体内功能，我们创造了携带Truss等位基因的小鼠，以允许有条件的Truss缺失。在初步研究中，我们已经证明这些小鼠在Truss位点进行了Cre介导的重组，导致Truss缺陷。我们的初步研究还表明，Truss-/-小鼠对肿瘤坏死因子-R1信号诱导的肝细胞凋亡和急性肝功能衰竭具有保护作用。现在有必要进行更多的研究，以探索这些最近创造和验证的小鼠的表型。这一探索性/发展性R21应用的目标是：(I)评估肝细胞和内皮细胞条件性Truss缺陷对肿瘤坏死因子-R1诱导的肝细胞凋亡和急性肝炎的影响，以及(Ii)检验Truss通过促进持续的JNK激活来增强肿瘤坏死因子-R1诱导的细胞凋亡的假设。这些目标将通过两个具体目标来实现。利用全球Truss缺陷小鼠、肝细胞特异性Truss缺陷小鼠和内皮细胞特异性Truss缺陷小鼠，特定目标1将检验肝细胞凋亡和急性致死性肝炎依赖于Truss的假设。特异目的2将验证这样的假设，即Truss在肿瘤坏死因子-R1诱导的肝细胞凋亡中的要求是促进持续的JNK激活，而JNK又通过线粒体途径激活caspase。据我们所知，这项建议中描述的绒毛桁架老鼠是我们实验室独有的。所提出的研究将为体内Truss功能提供新的见解，并将形成新的R01应用的基础。其他人最近的研究也表明特拉斯与阿尔茨海默氏症以及乳腺癌和肺癌有关。因此，除了上面概述的目标外，我们的目标是让其他研究人员可以使用这些小鼠，他们的工作重点是这个未被研究的基因。