KALLIKREIN AND VASCULAR DISEASE RISK IN DIABETES

激肽释放酶和糖尿病中的血管疾病风险

• 批准号: 7907550
• 负责人: AYAD A JAFFA
• 金额: $ 31万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-29 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907550
• 关键词: Affect; Albumins; Albuminuria; Animals; Apolipoprotein E; Apoptosis; Atherosclerosis; Blood Vessels; Bradykinin B2 Receptor; Cell physiology; Chronic; Clinical; Code; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Disease model; Epidermal Growth Factor Receptor; Excretory function; Family; Fostering; Genes; Genetic Determinism; Genetic Polymorphism; Goals; Health; High-Molecular-Weight Kininogen; Hyperglycemia; Hypertension; Injury; Insulin-Dependent Diabetes Mellitus; Kallikrein-Kinin System; Kidney; Kidney Diseases; Kininogenase; Knockout Mice; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Lead; Lesion; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; MAP Kinase Gene; Measurement; Medial; Microalbuminuria; Molecular; Morbidity - disease rate; Morphology; Mus; Outcome; Phosphorylation; Plasma Kallikrein; Play; Prekallikrein; Process; Promoter Regions; Prostate-Specific Antigen; Proteinase-Activated Receptors; Receptor Activation; Regression Analysis; Regulation; Risk; Risk Factors; Risk Marker; Role; Signal Transduction; Signal Transduction Pathway; Single Nucleotide Polymorphism; Smooth Muscle; Smooth Muscle Myocytes; Surrogate Markers; Survival Analysis; Testing; Thick; Time; Transactivation; Triglycerides; United States; Vascular Diseases; Vascular remodeling; base; cardiovascular risk factor; cohort; diabetic; diabetic patient; disorder risk; dyslipoproteinemia; genetic variant; hazard; insight; intima media; kidney vascular structure; macrovascular disease; mortality; novel; promoter; receptor; response; trend; type I diabetic; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): The risk factors that contribute to the development of vascular disease in diabetes are not fully defined. This proposal focuses on defining the role of plasma prekallikrein (PK) in the initiation and progression of vascular disease in type 1 diabetes, and on describing the molecular determinants of plasma PK that foster the development of diabetic vascular complications. Exciting new information has been generated by the PI from clinical, animal and basic studies on novel mechanisms and functions of plasma PK. Preliminary studies based on cross-sectional data generated from the DCCT/EDIC-cohort of type 1 diabetic patients, demonstrated an independent association between plasma PK and microalbuminuria, hypertension and elevated lipids. Multivariable regression analysis provided the first evidence of an independent and positive association between plasma PK levels and common and internal carotid intima medial thickness. A novel polymorphism (SNP) in the coding region of the plasma PK gene was identified. Survival analyses demonstrated that the onset of microalbuminuria occurs at a more rapid rate in diabetic subjects with the SNP than without the SNP. Finally, we discovered a novel mechanism of plasma PK activation by vascular smooth muscle cells (VSMC). Once activated, plasma kallikrein stimulates MAPK phosphorylation via transactivation of the epidermal growth factor receptor and induces apoptosis of VSMC. We hypothesize that, increased levels of plasma PK are a result of the diabetic state and play a pivotal role in the initiation and progression of diabetic vascular disease. To test this hypothesis, we propose the following specific aims: 1) To determine whether type 1 diabetic patients who develop renal and vascular disease have antecedent increases in the levels of plasma PK compared with type 1 diabetic patients who do not develop renal and vascular disease. 2) To determine the role of plasma prekallikrein in the initiation and progression of atherosclerosis and nephropathy in diabetic Apolipoprotein E (ApoE-/-) null mice. 3) To elucidate the cellular and molecular mechanisms underlying vascular remodeling in response to plasma prekallikrein stimulation. The proposed studies should establish plasma PK as a pathologically-important risk factor for vascular disease. Mechanistically, the proposed studies should generate significant insights into novel aspects of plasma PK signal transduction and regulation of vascular disease in diabetes. The health related significance of vascular disease and vascular disease risk in diabetes cannot be overstated. It is the leading cause of morbidity and mortality in the United States. The goals of this proposal are to elucidate risk markers and mechanisms of vascular disease that are operative in diabetes and to elucidate underlying molecular, cellular and genetic determinants of vascular complications of diabetes.

描述（由申请人提供）：导致糖尿病血管疾病发展的风险因素尚未完全确定。该提案的重点是定义血浆前激肽释放酶（PK）在1型糖尿病血管疾病的发生和进展中的作用，并描述促进糖尿病血管并发症发展的血浆PK的分子决定因素。PI从关于血浆PK新机制和功能的临床、动物和基础研究中获得了令人兴奋的新信息。基于1型糖尿病患者DCCT/EDIC队列生成的横断面数据的初步研究表明，血浆PK与微量白蛋白尿、高血压和血脂升高之间存在独立相关性。多变量回归分析提供了血浆PK水平与颈总动脉和颈内动脉内膜中层厚度之间独立和正相关的第一个证据。在血浆PK基因编码区发现了一种新的多态性（SNP）。生存分析表明，发生微量白蛋白尿的发生率更快，在糖尿病受试者与SNP比没有SNP。最后，我们发现了血管平滑肌细胞（VSMC）激活血浆PK的新机制。一旦激活，血浆激肽释放酶通过表皮生长因子受体的反式激活刺激MAPK磷酸化并诱导VSMC凋亡。我们假设，血浆PK水平升高是糖尿病状态的结果，在糖尿病血管疾病的发生和进展中起关键作用。为了检验这一假设，我们提出了以下具体目标：1）确定与未发生肾脏和血管疾病的1型糖尿病患者相比，发生肾脏和血管疾病的1型糖尿病患者的血浆PK水平是否有先前的增加。2)确定血浆前激肽释放酶在糖尿病载脂蛋白E（ApoE-/-）基因敲除小鼠动脉粥样硬化和肾病发生和发展中的作用。3)阐明血浆前激肽释放酶刺激引起血管重塑的细胞和分子机制。拟定的研究应确定血浆PK是血管疾病的重要病理学风险因素。从机制上讲，拟议的研究应该产生对血浆PK信号转导和糖尿病血管疾病调节的新方面的重要见解。糖尿病血管疾病和血管疾病风险与健康相关的重要性怎么强调都不为过。它是美国发病率和死亡率的主要原因。该提案的目标是阐明糖尿病血管疾病的风险标志物和机制，并阐明糖尿病血管并发症的潜在分子，细胞和遗传决定因素。