CRP, Diabetes, Atherothrombosis

CRP、糖尿病、动脉粥样硬化

基本信息

批准号：
7735729
负责人：
Ishwarlal Jialal
金额：
$ 45.61万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7735729
关键词：
Address Adhesions Antisense Oligonucleotides Area Atherosclerosis Biological Biological Markers Blood Vessels C-reactive protein Cardiovascular Diseases Clinical Coagulants Collaborations Complications of Diabetes Mellitus Coronary Data Development Diabetes Mellitus Endothelial Cells Epidemic Gelatinase B Human IgG Receptors In Vitro Inbred BB Rats Inflammation Inflammatory Injection of therapeutic agent Insulin-Dependent Diabetes Mellitus Lead MAP Kinase Gene MAPK14 gene MAPK8 gene Matrix Metalloproteinases Medial Mediator of activation protein Modeling Molecular NADPH Oxidase Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathway interactions Patients Phenotype Play Protein Kinase C Publishing Rattus Reactive Oxygen Species Reporting Research Personnel Role Rose Bengal Small Interfering RNA Superoxides Surrogate Markers Testing Thick Thromboplastin Thrombosis Up-Regulation Vascular Diseases Wistar Rats atherothrombosis base cardiovascular disorder risk cytokine diabetic diabetic cardiomyopathy diabetic rat ferric chloride in vivo inhibitor/antagonist macrophage monocyte mortality novel oxidized low density lipoprotein prevent shear stress uptake

项目摘要

In the previous proposal, the central hypothesis was to determine if CRP promotes atherothrombosis by effects on both endothelial cells and monocytes. We have now executed all four aims of this proposal and have advanced the field with regards to the vascular effects of CRP. In summary, we have elucidated the molecular mechanism by which CRP inhibits eNOS (in-vitro and in-vivo), we have documented the role of Fc-gamma receptors in the biological effects of CRP on endothelial cells, macrophages and in Wistar rats. Furthermore, we have elucidated the mechanism of CRPinduced monocyte adhesion under shear stress, and finally we have confirmed in-vivo, in Wistar rats, that CRP has effects that promote atherosclerosis including stimulation of NADPH-oxidase, superoxide, MPO release, oxidized LDL uptake, tissue factor, MMP-9 release from macrophages and decreased vasoreactivity. Diabetes is a proinflammatory state that is characterized by high CRP levels. However, there is a paucity of data examining the role of CRP in promoting the pro-inflammatory state in diabetes. We have shown in exciting and novel preliminary data that CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu (spontaneously diabetic BB rat). Thus, in this competing renewal, we wish to further explore the effects of CRP on diabetes and atherothrombosis. To this end, we are proposing two specific aims. In specific aim 1, we will continue to expand our exciting preliminary findings that CRP accentuates the pro-inflammatory, pro-oxidant state in the diabetic BB rat. In this model, we will confirm if CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu and also elucidate the molecular mechanism (s) by which CRP exerts these effects by employing in-vivo siRNA and antisense oligonucleotides to the different pathways identified. Based on findings largely from our group and others, that CRP promotes a pro-coagulant phenotype, in Specific Aim 2, using the spontaneously diabetic BB rat, we will now test in-vivo the effect of CRP on thrombosis in the diabetic milieu. Also, we will elucidate the mechanism (s) by which CRP promotes atherothrombosis in the diabetic state. We believe these studies will provide further novel data in support of the hypothesis that CRP promotes atherothrombosis in-vivo and a procoagulant, pro-inflammatory phenotype in diabetes. Probing into the molecular mechanisms by which CRP augments oxidative stress and inflammation in the diabetic milieu will eventually lead to therapies targeted at reducing inflammation and oxidative stress in diabetes and resulting in a decrease in vasculopathies

在之前的提议中，中心假设是确定 CRP 是否通过对两者的影响而促进动脉粥样硬化血栓形成内皮细胞和单核细胞。我们现在已经实现了该提案的所有四个目标，并推进了该领域的发展关于 CRP 的血管作用。综上所述，我们阐明了CRP的分子机制。抑制 eNOS（体外和体内），我们已经记录了 Fc-gamma 受体在生物效应中的作用 CRP 对内皮细胞、巨噬细胞和 Wistar 大鼠的影响。此外，我们还阐明了CRP诱导的机制。剪切应力下的单核细胞粘附，最后我们在 Wistar 大鼠体内证实了 CRP 促进动脉粥样硬化的作用，包括刺激 NADPH 氧化酶、超氧化物、MPO 释放、氧化 LDL 摄取、组织因子、巨噬细胞释放 MMP-9 以及血管反应性降低。糖尿病是一种促炎性疾病以高 CRP 水平为特征的状态。然而，缺乏数据来检验其作用 CRP 促进糖尿病的促炎状态。我们通过令人兴奋且新颖的初步数据表明 CRP 会加剧糖尿病环境中的体内促炎、促氧化作用（自发性糖尿病 BB 鼠）。因此，在这场竞争更新中，我们希望进一步探讨 CRP 对糖尿病和动脉粥样硬化血栓形成的影响。为此，我们提出两个具体目标。在具体目标 1 中，我们将继续扩展我们令人兴奋的初步发现，CRP 会加剧糖尿病 BB 大鼠的促炎、促氧化状态。在这个模型，我们将确认 CRP 是否会加剧糖尿病环境中的体内促炎、促氧化作用并通过体内 siRNA 阐明 CRP 发挥这些作用的分子机制反义寡核苷酸识别出不同的途径。主要基于我们小组和其他人的研究结果， CRP 促进促凝血表型，在具体目标 2 中，使用自发性糖尿病 BB 大鼠，我们将现在在体内测试 CRP 对糖尿病环境中血栓形成的影响。此外，我们将通过以下方式阐明其机制：其中CRP在糖尿病状态下促进动脉粥样硬化血栓形成。我们相信这些研究将提供进一步的新颖数据支持以下假设：CRP 促进体内动脉粥样硬化血栓形成，并且是一种促凝血、促炎剂糖尿病的表型。探讨CRP增强氧化应激的分子机制糖尿病环境中的炎症最终将导致针对减少炎症和氧化的治疗糖尿病压力并导致血管病变减少