GPCR Signaling Through a Novel NF-kB Pathway

通过新型 NF-kB 通路的 GPCR 信号传导

基本信息

批准号：
9211376
负责人：
PETER C LUCAS
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211376
关键词：
Acids Adverse event Agonist Amination Amines Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Arterial Fatty Streak Atherosclerosis Binding Biochemical Biophysical Process Blood Vessels Blood capillaries CXCL12 gene Cardiovascular Diseases Cellular biology Data Deposition Development Disease Endothelial Cells Endothelin-1 Endothelium Enzymes Exposure to Family Functional disorder Funding Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Glycoproteins Goals Human IL8 gene Inflammation Inflammatory Knowledge Lead Ligands Link Lipids MAPK8 gene Mediating Mediator of activation protein Modality Molecular Movement Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mus NF-kappa B Organism Outcome Pathologic Processes Pathway interactions Peptide Hydrolases Peptides Permeability Pharmacologic Substance Pharmacology Plant Roots Positioning Attribute Process Proteins Receptor Activation Recruitment Activity Role Rupture Signal Transduction Signal Transduction Pathway Smooth Muscle Source Stromal Cell-Derived Factor 1 Surface Testing Therapeutic Therapeutic Intervention Thrombin Thrombosis Vascular Diseases Work atherogenesis base capillary clinical application design endothelial dysfunction in vivo inflammatory milieu inhibitor/antagonist innovation leukocyte activation lysophosphatidic acid mouse model novel prevent public health relevance receptor response shear stress small molecule therapeutic candidate therapeutic target transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Vascular inflammation is a critical contributing factor to the development of atherosclerosis. Combined with the effects of lipid deposition, inflammation promotes endothelial dysfunction, smooth muscle proliferation, and matrix destabilization, adverse events that exacerbate developing atherosclerotic lesions and may ultimate lead to their rupture and to vessel thrombosis. The sources of inflammation are varied, but among the most important are the circulating substances that stimulate G protein-coupled receptors (GPCRs) present on the surface of endothelial cells. These include a diverse array of peptide ligands, amines, glycoproteins and enzymes. The activated receptors then relay intracellular signals by stimulating multiple pathways, including those for ERK, Akt, JNK, p38MAPK, and STAT, but activation of the NF-kB transcription factor has been deemed one of the most important and potent pro-inflammatory signals. We have uncovered a signal transduction pathway that mediates NF-kB activation in response to the GPCR agonists, Angiotensin II and thrombin. This pathway centers on the assembly of a multiprotein signaling module composed of the molecules CARMA3, Bcl10, and MALT1, which we now refer to as the "CBM signalosome". In this signalosome, the MALT1 protein acts as the primary effector, coordinating downstream stimulation of the canonical NF-kB machinery. It appears that this CBM signalosome is also critical for NF-kB activation induced by GPCRs that recognize lsyophosphatidic acid (LPA), IL-8, endothelin-1, and SDF-1/CXCL12. Most of these substances have been clearly linked to vascular dysfunction, inflammation, and atherogenesis, and it is thought that their ability to activate NF-kB is central to these pathophysiologic responses. Thus, we believe the CBM signalosome is a mechanistic hub responsible for relaying proinflammatory signals in the vessel wall, since it is stimulated by such a diverse array of GPCR agonists. As such, targeting the actions of the signalosome may prove to be a highly effective strategy for managing atherogenesis. In this proposal, we will probe the mechanistic links between the CBM signalosome and specific aspects of vascular pathobiology. This will be accomplished through three specific aims that (1) investigate the effect of blocking CBM activity on NF-kB activation in endothelial cells and novel aspects of endothelial pathophysiology, (2) explore the mechanisms whereby the CBM signalosome is assembled following GPCR activation, and (3) test the effect of blocking CBM activity on the atherogenic process in vivo. We anticipate that the results will broadly inform development of pharmaceutical strategies for curtailing the contributions of inflammation to atherogenesis.

描述（由申请人提供）：血管炎症是导致动脉粥样硬化发展的关键因素。结合脂质沉积的作用，炎症促进了内皮功能障碍，平滑肌增殖和基质破坏稳定，不良事件加剧了发展动脉粥样硬化病变，并可能最终导致其破裂和血管血栓形成。炎症的来源各不相同，但最重要的是刺激内皮细胞表面上存在G蛋白偶联受体（GPCR）的循环物质。这些包括各种各样的肽配体，胺，糖蛋白和酶。然后，激活的受体通过刺激多种途径（包括ERK，AKT，JNK，P38MAPK和STAT）来中继细胞内信号，但是NF-KB转录因子的激活被认为是最重要且最有效的促促促疾病信号之一。我们发现了一种信号转导途径，该途径响应GPCR激动剂，血管紧张素II和凝血酶介导NF-KB激活。该途径集中在由CARMA3，BCL10和MALT1组成的多蛋白信号模块的组装上，我们现在称为“ CBM信号体”。在此信号体中，MALT1蛋白充当主要效应子，协调了规范NF-KB机械的下游刺激。看来该CBM信号体对于识别甲状腺磷酸酸（LPA），IL-8，内皮素-1和SDF-1/CXCL12引起的NF-KB激活也至关重要。这些物质中的大多数都与血管功能障碍，炎症和动脉粥样硬化有关，并且人们认为它们激活NF-KB的能力对于这些病理生理反应至关重要。因此，我们认为CBM信号体是负责在容器壁中传递促炎信号的机械中心，因为它受到了如此多样的GPCR激动剂的刺激。因此，靶向信号体的作用可能被证明是管理动脉粥样硬化的高效策略。在此提案中，我们将探测CBM信号体和血管病理学特定方面之间的机械联系。这将通过三个特定目的来实现（1）研究阻断CBM活动对NF-KB激活的影响内皮细胞和内皮病理生理学的新方面（2）探讨了GPCR激活后CBM信号体组装CBM信号体的机制，（3）测试阻断CBM活性对体内动脉粥样硬化过程的影响。我们预计结果将广泛地为制定药物策略的发展，以减少炎症对动脉粥样硬化的贡献。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MALT1 protease: a new therapeutic target in B lymphoma and beyond?

DOI：
10.1158/1078-0432.ccr-11-0467
发表时间：
2011-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
McAllister-Lucas LM;Baens M;Lucas PC
通讯作者：
Lucas PC

CARMA3 Is a Critical Mediator of G Protein-Coupled Receptor and Receptor Tyrosine Kinase-Driven Solid Tumor Pathogenesis.