Angiotensin II Signaling Through A Novel NF-kB Pathway

通过新型 NF-kB 通路的血管紧张素 II 信号传导

• 批准号: 7780019
• 负责人: PETER C LUCAS
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7780019
• 关键词: Accounting; Acute; Address; Adverse effects; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Animal Experiments; Animal Feed; Animals; Arteries; Atherosclerosis; Biochemical; Bioinformatics; Biological Assay; Biological Models; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cell model; Cells; Chronic; Complex; Coronary artery; Critiques; Data; Development; Endothelial Cells; Evaluation; Event; Exposure to; Functional disorder; G-Protein-Coupled Receptors; Growth Factor; Human; Hypertension; Immunoprecipitation; In Vitro; Inflammation Mediators; Inflammatory; Inflammatory Response; Infusion procedures; Knockout Mice; Knowledge; Laboratories; Lead; Ligands; Link; Lymphocyte; Mediating; Messenger RNA; Methods; Modeling; Molecular; Muscle; NF-kappa B; Pathologic; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiological; Protein Isoforms; Protein Kinase C; Proteins; Rattus; Receptor Activation; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Protein; Site; Smooth Muscle; Smooth Muscle Myocytes; Suggestion; Testing; Time; Tissues; base; cytokine; design; experience; improved; in vivo; in vivo Model; macrophage; member; novel; overexpression; peptide hormone; prevent; receptor; research study; response; success; transcription factor

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) has recently become recognized as a powerful pro-inflammatory mediator. Although originally appreciated for its critical role in regulating blood pressure, this peptide hormone is now known to stimulate inflammatory pathways in numerous tissues, including the heart and arteries. Chronic exposure to Ang II may then lead to a variety of pathologic conditions related to a heightened inflammatory state. Perhaps the best example is in muscular arteries, where Ang II contributes to the development of atherosclerosis by stimulating the recruitment of macrophages and other inflammatory cells, stimulating smooth muscle proliferation and activation, and promoting endothelial dysfunction. The principal receptor for Ang II (AT1R) is a member of the G protein-coupled receptor superfamily. Numerous signaling pathways are initiated following ligand activation of this receptor, but stimulation of the NF-:B transcription factor appears to underlie most of the pro-inflammatory effects of Ang II. Importantly, while activation of protein kinase C (PKC) is a prerequisite for this effect, very little is known about the intermediate steps that bridge Ang II-dependent PKC activation with the eventual stimulation of NF-:B. However, our preliminary data now reveal a molecular link to explain this phenomenon. Our data indicate that a scaffolding protein (CARMA3) serves to integrate an upstream signal from PKC with the downstream effector proteins, Bcl10 and MALT1, which together stimulate a canonical pathway for NF-:B activation. We propose to explore the physiologic and biochemical implications of this signaling pathway through 4 aims: (1) Identify the molecular mechanism by which the AT1 receptor communicates with CARMA3. (2) Identify the molecular mechanism by which the IKK complex is activated following Ang II stimulation. (3) Test the role of CARMA3, Bcl10, and MALT1 in mediating Ang II-dependent inflammatory responses in endothelial and vascular smooth muscle cells. (4) Test the role of CARMA3 in mediating Ang II-dependent cardiovascular pathology, through analysis of CARMA3 knockout mice. Project Relevance: Ang II-dependent hypertension is a major contributing factor to cardiovascular disease. Understanding the pro-inflammatory, intracellular signaling events activated by Ang II is critical for our ability to eventually control the adverse effects of Ang II. Detailed knowledge of these signaling events will allow for the rational design of pharmacologic agents to target these events.

描述（由申请人提供）：血管紧张素II（Ang II）最近被认为是一种强大的促炎介质。虽然最初被认为是调节血压的关键作用，但这种肽激素现在已知会刺激许多组织中的炎症途径，包括心脏和动脉。长期暴露于血管紧张素II，然后可能导致各种病理条件相关的炎症状态升高。也许最好的例子是在肌肉动脉中，其中Ang II通过刺激巨噬细胞和其他炎性细胞的募集、刺激平滑肌增殖和活化以及促进内皮功能障碍而促成动脉粥样硬化的发展。血管紧张素II的主要受体（AT 1 R）是G蛋白偶联受体超家族的成员。许多信号传导途径在配体激活该受体后启动，但NF-：B转录因子的刺激似乎是Ang II的大部分促炎作用的基础。重要的是，虽然蛋白激酶C（PKC）的活化是这种效应的先决条件，但对连接Ang II依赖性PKC活化与NF-：B最终刺激的中间步骤知之甚少。然而，我们的初步数据现在揭示了一种分子联系来解释这种现象。我们的数据表明，支架蛋白（CARMA 3）的作用是整合上游信号从PKC与下游效应蛋白，Bcl 10和MALT 1，共同刺激NF-：B激活的经典途径。本研究拟从以下4个方面探讨该信号通路的生理生化意义：（1）研究AT 1受体与CARMA 3之间的信号转导机制。(2)确定IKK复合物在Ang II刺激后被激活的分子机制。(3)检测CARMA 3、Bcl 10和MALT 1在内皮细胞和血管平滑肌细胞中介导Ang II依赖性炎症反应中的作用。(4)通过分析CARMA 3敲除小鼠，测试CARMA 3在介导Ang II依赖性心血管病理学中的作用。 项目相关性：血管紧张素II依赖性高血压是心血管疾病的主要促发因素。了解促炎性，细胞内信号事件激活的血管紧张素II是至关重要的，我们的能力，最终控制血管紧张素II的不良反应。这些信号事件的详细知识将允许合理设计的药物，以针对这些事件。