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: 7690914
• 负责人: AYAD A JAFFA
• 金额: $ 31.64万
• 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/7690914
• 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）：尚未完全定义导致糖尿病血管疾病发展的危险因素。该提案的重点是定义血浆前卡利克林（PK）在1型糖尿病中血管疾病的起始和进展中的作用，并描述血浆PK的分子决定因素，从而促进糖尿病血管并发性的发展。 PI由临床，动物和基础研究产生了有关等离子体PK的新机制和功能的PI。基于从1型糖尿病患者的DCCT/EDIC-COHORT产生的横截面数据的初步研究表明，血浆PK与微量白蛋白尿，高血压和脂质升高之间存在独立的关联。多变量回归分析提供了血浆PK水平与常见和内部颈内内侧厚度之间独立和正相关的第一个证据。鉴定了等离子体PK基因编码区域中的一种新型多态性（SNP）。生存分析表明，与没有SNP相比，与SNP相比，微量白蛋白尿的发作在糖尿病受试者中以更快的速度发生。最后，我们发现了血浆平滑肌细胞（VSMC）的血浆PK激活的新型机制。激活后，血浆Kallikrein通过反式激活因子受体的反式激活刺激MAPK磷酸化，并诱导VSMC的凋亡。我们假设，等离子体PK的水平升高是糖尿病状态的结果，并且在糖尿病血管疾病的起始和进展中起关键作用。为了检验这一假设，我们提出以下具体目的：1）确定患有肾脏和血管疾病的1型糖尿病患者是否在血浆PK水平上是否与不患有肾脏和血管疾病的1型糖尿病患者相比，血浆PK的水平有所增加。 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）阐明血浆重塑的细胞和分子机制，响应血浆predikalikrein刺激。拟议的研究应建立等离子体PK作为血管疾病的病理危险因素。从机械上讲，拟议的研究应对血浆PK信号转导的新方面和糖尿病血管疾病的调节产生重大见解。血管疾病和血管疾病风险在糖尿病中的重要意义不能被夸大。它是美国发病和死亡率的主要原因。该提案的目标是阐明在糖尿病中起作用的血管疾病的风险标记和机制，并阐明糖尿病血管并发症的基本分子，细胞和遗传决定因素。