Role of Polarity Complex Signaling on Non-muscle Myosin in Intestinal Epithelia

极性复合信号传导对肠上皮非肌肉肌球蛋白的作用

• 批准号: 8665925
• 负责人: RADIA FORTEZA
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665925
• 关键词: Affect; American; Animal Model; Antibodies; Apical; Area; Binding; Biomedical Research; C-terminal; Caco-2 Cells; Cell Line; Cell Polarity; Chronic; Co-Immunoprecipitations; Colitis; Colorectal; Complement; Complex; Crohn' s disease; Data; Disease; Down-Regulation; Epithelial; Epithelial Cells; Epithelium; Experimental Models; First Degree Relative; Future; Goals; Health; Human; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intervention; Intestines; Investigation; Knockout Mice; Laboratories; Learning; Light; Maintenance; Mass Spectrum Analysis; Measurement; Mediating; Molecular; Molecular Biology; Molecular Weight; Myosin Light Chain Kinase; Myosin Light Chains; Myosin Type II; N-terminal; Nonmuscle Myosin Type IIA; Pathogenesis; Pathway interactions; Patients; Peptides; Permeability; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Predisposing Factor; Protein Isoforms; Proteins; Publishing; Relapse; Relative (related person); Reporting; Resistance; Risk; Role; Side; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stimulus; Structure; TNF gene; Testing; Therapeutic Intervention; Tight Junctions; Tracer; Training; Transgenic Animals; Ulcerative Colitis; Up-Regulation; Work; base; body system; career; cytokine; design; economic impact; human disease; intestinal epithelium; mimetics; mouse model; mutant; non-muscle myosin; novel; overexpression; research study; response

DESCRIPTION (provided by applicant): Our laboratory recently reported that the "polarity complex" (atypical PKC-Par3-Par6), an evolutionarily conserved signaling pathway is deeply downregulated under inflammatory TNF signaling. It is also downregulated in a mouse model of colitis as well as in ulcerative colitis and Crohn's disease patients. Because Inflammatory Bowel Disease represents a substantial problem for human health, I would like to further analyze the downstream consequences of aPKC downregulation. Our published and preliminary data show that the polarity complex exerts antagonistic control on the activation of non-muscle Myosin IIA, a broadly accepted effector of inflammatory signaling in epithelial cells. Other laboratories have shown the involvement of nmMyosin II in tight junction maintenance and downstream of inflammatory signaling, but we are the first to postulate specifically one of the isoforms nmMyoIIA as the main molecular mechanism controlling epithelial barrier. Accordingly, here I put forth the hypothesis that: Inflammation-dependent downregulation of the polarity complex aPKC is a novel signaling mechanism that synergistically upregulates the apical expression of nmMyosinIIA abrogating direct phosphorylation of the heavy chains. This project is devoted to analyze the effects and the molecular mechanisms by which aPKC-Par3-Par6 antagonizes MLCK- mediated nmMyosin II activation.

描述（由申请人提供）：我们的实验室最近报道，“极性复合物”（非典型PKC-Par3-Par6）是一种进化上保守的信号通路，在炎症TNF信号传导下深度下调。它在结肠炎小鼠模型以及溃疡性结肠炎和克罗恩病患者中也被下调。 由于炎症性肠病对人类健康构成重大问题，因此我想进一步分析 aPKC 下调的下游后果。我们发表的初步数据表明，极性复合物对非肌肉肌球蛋白 IIA 的激活发挥拮抗控制作用，肌球蛋白 IIA 是上皮细胞中广泛接受的炎症信号传导效应物。其他实验室已证明 nmMyosin II 参与紧密连接 炎症信号传导的维持和下游，但我们是第一个专门假设其中一种亚型 nmMyoIIA 作为控制上皮屏障的主要分子机制。因此，我在此提出假设：极性复合物 aPKC 的炎症依赖性下调是一种新的信号传导机制，可协同上调 nmMyosinIIA 的顶端表达，从而消除重链的直接磷酸化。该项目致力于分析aPKC-Par3-Par6拮抗MLCK介导的nmMyosin II激活的作用和分子机制。