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

基本信息

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
项目类别：
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

项目摘要

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）最近被公认为是强大的促炎性介体。尽管最初因其在调节血压中的关键作用而受到赞赏，但现在已知这种肽激素刺激包括心脏和动脉在内的许多组织中的炎症途径。然后，长期暴露于ANG II可能会导致与炎症状态增强有关的多种病理状况。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症细胞的募集来促进动脉粥样硬化的发展，从而刺激平滑肌增殖和激活，并促进内皮功能障碍。 ANG II（AT1R）的主要受体是G蛋白偶联受体超家族的成员。在该受体的配体激活后，启动了许多信号通路，但是对NF-：B转录因子的刺激似乎是ANG II的大多数促炎作用的基础。重要的是，虽然蛋白激酶C（PKC）的激活是这种效果的先决条件，但对桥接ang ang II依赖性PKC激活而最终刺激NF-的中间步骤知之甚少。但是，我们的初步数据现在揭示了一种分子链接来解释这种现象。我们的数据表明，脚手架蛋白（CARMA3）用来将PKC的上游信号与下游效应蛋白Bcl10和Malt1整合在一起，从而刺激了NF-：B激活的规范途径。我们建议通过4个目标探索该信号通路的生理和生化含义：（1）确定AT1受体与CARMA3通信的分子机制。（2）确定在ANG II刺激后激活IKK复合物的分子机制。（3）测试CARMA3，BCL10和MALT1在内皮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CARMA3基因敲除小鼠，测试CARMA3在介导ANG II依赖性心血管病理学中的作用。项目相关性：ANG II依赖性高血压是导致心血管疾病的主要因素。了解ANG II激活的促炎性，细胞内信号传导事件对于我们最终控制ANG II的不良反应的能力至关重要。这些信号事件的详细知识将允许药理学剂的合理设计针对这些事件。