Molecular Determinants of Arterial Remodeling in Atherogenesis

动脉粥样硬化中动脉重塑的分子决定因素

• 批准号: 7781064
• 负责人: Peter Libby
• 金额: $ 42.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781064
• 关键词: Abdominal Aortic Aneurysm; Acute; Acute myocardial infarction; Affect; Amino Acids; Aneurysm; Angiotensin II; Animals; Aortic Aneurysm; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological; Biological Markers; Blood Vessels; Blood specimen; Cardiomyopathies; Cardiovascular system; Catabolism; Cathepsins; Cells; Clinical; Collagen; Complement component C1s; Conduct Clinical Trials; Coronary; Disease; Dose; Elastases; Elastin; Enzymes; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Family; Gelatinase B; Genetic; Human; Image; Imaging technology; In Vitro; Infusion procedures; Institution; Interstitial Collagenase; Intervention; Lesion; Leukocyte Elastase; Matrix Metalloproteinases; Measurement; Medicine; Metabolism; Microscopy; Mineralocorticoid Receptor; Molecular; Mus; Mutant Strains Mice; Mutation; Neuraxis; Neutrophil Collagenase; Niemann-Pick Diseases; Optics; Pathogenesis; Pathological Dilatation; Patients; Pilot Projects; Predisposition; Preparation; Preventive; Prions; Proteins; Regulation; Role; Sampling; Series; Specimen; Structure; Techniques; Testing; Thrombosis; Tissues; Translating; Translational Research; United States National Institutes of Health; Validation; arterial remodeling; atherogenesis; cathepsin K; collagenase; collagenase 3; genetic manipulation; human MMP14 protein; imaging modality; in vivo; inhibitor/antagonist; insight; molecular imaging; mutant; neurodegenerative phenotype; novel; novel marker; optical polarization; overexpression; patient population; pre-clinical; preclinical study; programs; promoter; protein degradation; public health relevance; receptor; research study; response; stressor; tool; two-photon

DESCRIPTION (provided by applicant): Activated cells in human coronary atheromata express high levels of matrix-degrading enzymes, e.g., collagenases and elastases. Our previous studies suggested that such collagenolytic and elastolytic activities regulate the integrity of diseased arteries. A series of recent studies supported by this NIH R01 provided the direct in vivo evidence for the important role of collagenolytic enzymes of the matrix metalloproteinase (MMP) family in arterial remodeling. This renewal application proposes to examine further the effects of genetic and pharmacologic manipulations of collagenases on plaque collagen metabolism, and to study in depth the role of elastolytic enzymes in arterial disease. We will also explore the possibility of detecting matrix degradation using biomarkers. Specific Aim 1 will complete our studies of the roles of various interstitial collagenases in the regulation of the structure of atherosclerotic plaques in mice. We will examine the effects of deficiency of another collagenase MMP-8 on plaque structure. We will further analyze collagen structure in atheromata of the compound mutant mice lacking two major collagenases MMP-13 and MMP-8. Studies using a novel imaging technology and an MMP-13 selective inhibitor will test the hypothesis that pharmacologic inhibition of this collagenase will alter the plaque structure. Specific Aim 2 will test the hypothesis that mice with combined deficiency of apoE and Niemann Pick disease, type C1 (NPC1) protein will show heightened susceptibility to arterial ectasia. As compound mutant apoE- and NPC1-deficient mice overexpress cathepsin K, a potent elastase, we will track cathepsin activity in vivo in these animals by molecular imaging. We will also image and characterize the structure of elastin in arterial tissue from these manipulated mutant mice. Specific Aim 3 will develop and validate biomarkers of extracellular matrix protein degradation to provide novel tools to probe elastin and collagen degradation in vivo. These markers will include MSGC measurement of post-translationally modified amino acids and their condensates that serve as signatures for elastin and collagen breakdown. Exploration of the in vivo utility of novel markers of elastinolysis will use biological specimens derived from mice with mutations in various elastases including cathepsins K and S, MMP-9 and -12, and neutrophil elastase, as well as from mice with genetically-induced cardiomyopathies. If we succeed in developing and validating novel biomarkers, we will apply them to banks of blood specimens on patients in various large clinical trials conducted at our institution to test the hypothesis that the interventions (e.g. mineralocorticid receptor blocking agent or statin administration) affect matrix metabolism in humans in vivo. PUBLIC HEALTH RELEVANCE: Collagenolytic and elastolytic activities in human coronary atheromata likely regulate the matrix structure of atherosclerotic plaques, a key determinant of the acute thrombotic complications. Our recent studies supported by this NIH R01 provided the direct in vivo evidence for the important role of collagenolytic enzymes. This renewal application proposes to examine further the effects of pharmacologic and genetic manipulations of collagenases on plaque collagen metabolism. We also propose to study in depth the role of elastolytic enzymes in the pathogenesis of arterial disease. In addition, we will explore the possibility of detecting matrix degradation using biomarkers. This project should help in understanding the mechanisms of arterial remodeling during atherogenesis. These complementary studies will translate further preclinical findings into clinical preventive cardiovascular medicine.

描述（由申请人提供）：人冠状动脉粥样硬化中的活化细胞表达高水平的基质降解酶，例如，胶原酶和弹性蛋白酶。我们以前的研究表明，这种胶原溶解和弹性蛋白溶解活性调节病变动脉的完整性。最近一系列由NIH R 01支持的研究为基质金属蛋白酶（MMP）家族的胶原溶解酶在动脉重塑中的重要作用提供了直接的体内证据。本更新申请建议进一步研究胶原酶的遗传和药理学操作对斑块胶原代谢的影响，并深入研究弹性蛋白溶解酶在动脉疾病中的作用。我们还将探索使用生物标志物检测基质降解的可能性。具体目标1将完成我们的各种间质胶原酶在调节小鼠动脉粥样硬化斑块结构中的作用的研究。我们将研究另一种胶原酶MMP-8缺乏对斑块结构的影响。我们将进一步分析缺乏两种主要胶原酶MMP-13和MMP-8的复合突变小鼠动脉粥样硬化中的胶原结构。使用新的成像技术和MMP-13选择性抑制剂的研究将测试这种胶原酶的药理学抑制将改变斑块结构的假设。具体目标2将检验以下假设：apoE和尼曼匹克病C1型（NPC 1）蛋白联合缺乏的小鼠对动脉扩张的易感性增加。由于复合突变体apoE-和NPC 1-缺陷小鼠过度表达组织蛋白酶K，一种有效的弹性蛋白酶，我们将跟踪组织蛋白酶活性在这些动物体内的分子成像。我们还将图像和特征的弹性蛋白在动脉组织从这些操纵突变小鼠的结构。具体目标3将开发和验证细胞外基质蛋白降解的生物标志物，以提供体内探测弹性蛋白和胶原蛋白降解的新工具。这些标志物将包括作为弹性蛋白和胶原分解标志的后修饰氨基酸及其缩合物的MSGC测量。弹性蛋白溶解的新标记物的体内效用的探索将使用来自在各种弹性蛋白酶（包括组织蛋白酶K和S、MMP-9和-12和中性粒细胞弹性蛋白酶）中具有突变的小鼠以及来自具有遗传诱导的心肌病的小鼠的生物标本。如果我们成功地开发和验证了新的生物标志物，我们将把它们应用于我们机构进行的各种大型临床试验中患者的血液标本库，以检验干预措施（例如，盐皮质激素受体阻断剂或他汀类药物给药）影响人体体内基质代谢的假设。 公共卫生相关性：人冠状动脉粥样硬化中的胶原溶解和弹性蛋白溶解活性可能调节动脉粥样硬化斑块的基质结构，这是急性血栓性并发症的关键决定因素。我们最近的研究得到了NIH R 01的支持，为胶原溶解酶的重要作用提供了直接的体内证据。该更新申请建议进一步检查胶原酶的药理学和遗传操作对斑块胶原代谢的影响。我们还建议深入研究弹性蛋白溶解酶在动脉疾病发病机制中的作用。此外，我们将探索使用生物标志物检测基质降解的可能性。本研究将有助于了解动脉粥样硬化形成过程中动脉重塑的机制。这些补充研究将进一步将临床前发现转化为临床预防心血管药物。