Characterization of mechanisms through which coagulation proteases differentially regulate hyperglycemia and hyperlipidemia induced accelerated atherosclerosis.

凝血蛋白酶差异调节高血糖和高脂血症诱导加速动脉粥样硬化的机制的表征。

基本信息

批准号：
61478778
负责人：
Professor Dr. Berend Isermann
金额：
--
依托单位：
Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/61478778?language=en
关键词：
Characterization mechanisms through coagulation proteases

项目摘要

The role of coagulation proteases, in particular protease dependent signalling, for the establishment of atherosclerosis is unknown. Thrombin and activated protein C (PC) are two key regulators of the coagulation system with opposing effects in regard to coagulation activation. They provoke differential intracellular signalling despite activation of the same receptor, protease activated receptor 1 (PAR-1). Activity of thrombin and activated PC is determined by the thrombin binding endothelial protein thrombomodulin (TM), which inhibits thrombin and activates PC. Thus, TM has a key role in determining activity of thrombin, activated PC and secondary effects mediated through these proteases. Expression of receptors for coagulation proteases (PAR´s, TM, EPCR (endothelial protein C receptor)) has been established in cell-types relevant for cardiovascular disease. However, the mechanisms through which TM, thrombin and activated PC evoke differential intracellular signalling and the relation to chronic cardiovascular disease are not understood. We have been able to show that TM modulates atherosclerosis and cardiac hypertrophy in vivo. In vitro results suggest that TM might modulate cellular function (e.g. NF-kB activation, expression of adhesion molecules) through two mechanisms: (A) inhibition of thrombin dependent cell activation and (B) promotion of activated PC dependent cytoprotection. The aim of the proposal is to identify the mechanism through which TM modulates differential cell activation and cardiovascular disease. Using in vivo and in vitro experiments we intend to: 1) Identify the mechanism through which thrombin and activated PC differentially regulate NF-kB activation and expression of adhesion molecules; 2) Determining whether TM has direct signalling properties; 3) Define the role of TM-dependent regulation of thrombin and activated PC for atherosclerosis in vivo; 4) Determine whether the TM-PC system regulates cardiac hypertrophy indirectly (via regulation of arterial blood pressure) or directly through receptor dependent mechanisms. The current proposal will provide an in depth analysis of the mechanisms through which thrombin, activated PC, and TM regulate cardiovascular disease. Animal models of accelerated atherosclerosis (high fat diet or hyperglycemia) and with genetically altered activity of the TM-PC system will be used. These in vivo experiments will be paired with complementary in vitro studies. The long term aim of the proposed studies is an in depth understanding of the mechanisms through which the coagulation system regulates cardiovascular disease. This work will lay ground for novel targeted therapeutic intervention based on the mechanisms regulated by coagulation proteases, but circumventing associated problems such as increased risk of hemorrhage.

凝血蛋白酶的作用，特别是蛋白酶依赖性信号传导，对于动脉粥样硬化的建立是未知的。凝血酶和活化蛋白C（PC）是凝血系统的两个关键调节剂，在凝血激活方面具有相反的作用。它们引起了同一受体蛋白酶活化受体1（PAR-1）的细胞内信号传导成功激活。凝血酶和激活PC的活性由凝血酶结合内皮蛋白血栓蛋白（TM）确定，该蛋白质血栓蛋白（TM）抑制凝血酶并激活PC。这在确定凝血酶活性PC的活性和通过这些蛋白酶介导的次级效应方面具有关键作用。在与心血管疾病有关的细胞类型中已经建立了凝血蛋白（PAR的，TM，EPCR（内皮蛋白C受体））的受体的表达。然而，尚不清楚TM，凝血酶和激活PC引起差异的细胞内信号传导以及与慢性心血管疾病的关系的机制。我们已经能够证明TM在体内调节动脉粥样硬化和心脏肥大。体外结果表明，TM可能通过两种机制来调节细胞功能（例如NF-KB激活，粘合分子的表达）：（a）抑制凝血酶依赖性细胞激活和（b）促进激活的PC依赖性细胞蛋白概要剂。该提案的目的是确定TM调节差异细胞激活和心血管疾病的机制。使用体内和体外实验，我们打算：1）确定凝血酶和激活的PC差异调节NF-KB激活和粘合分子表达的机制； 2）确定TM是否具有直接信号传导特性； 3）定义凝血酶和活化PC的TM依赖性调节在体内动脉粥样硬化的作用； 4）确定TM-PC系统是间接调节心脏肥大的（通过调节动脉血压）还是直接通过受体依赖机制来调节心脏肥大。当前的建议将对凝血酶，激活PC和TM调节心血管疾病的机制进行深入分析。加速动脉粥样硬化的动物模型（高脂肪饮食或高血糖），随着TM-PC系统的遗传活性，它们在体内实验的活性将与体外研究的完整性配对。拟议研究的长期目的是对凝血系统调节心血管疾病的机制的深入了解。这项工作将根据由凝血蛋白酶调节的机制进行新的针对性治疗干预的基础，但要规避相关问题，例如增加出血风险。