Macrovascular Dysfunction of Diabetes

糖尿病大血管功能障碍

基本信息

批准号：
7191672
负责人：
MARC Lee GOALSTONE
金额：
$ 17.14万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7191672
关键词：
1-Phosphatidylinositol 3-Kinase Acceleration Advanced Glycosylation End Products Angiotensin II Antiatherogenic Aorta Atherosclerosis Blood Vessels CREB1 gene Cell Adhesion Molecules Cells Cellular Membrane Cellular Structures Compensatory Hyperinsulinemia Condition Cysteine Cytoskeletal Gene DNA biosynthesis DNA chemical synthesis Development Diabetes Mellitus Dimethylallyltranstransferase Dominant-Negative Mutation E-Selectin EGF gene Endothelial Cells Enzymes FOS gene Family Figs - dietary Functional disorder Future Gene Expression Glucose Goals Growth Growth Factor Guanosine Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Hyperglycemia Hyperinsulinism Individual Insulin Insulin Resistance Insulin-Like Growth Factor I Intercellular adhesion molecule 1 JUN gene LY294002 Laboratories Lead Link Lung MAPK7 gene Mediating Membrane Messenger RNA Metabolic Mitogens Molecular Target Molecular Weight Mutate Nitric Oxide Synthase Nuclear Obesity Pathway interactions Pharmaceutical Preparations Phosphorylation Physiological Plasmids Platelet-Derived Growth Factor Protein Family Proteins Pulmonary artery structure Rattus Reactive Oxygen Species Regulation Research Personnel Resistance Role Signal Pathway Smooth Muscle Myocytes Stimulus Substrate Specificity System Testing Tetanus Helper Peptide Therapeutic Tissues Transactivation Transcriptional Activation Transferase Vascular Cell Adhesion Molecule-1 Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular Endothelium design farnesyltranstransferase in vivo inhibitor/antagonist insulin signaling kinase inhibitor migration mutant novel prenyl prenylation programs protein farnesyltransferase protein geranylgeranyltransferase ras Proteins research study response rho rho GTP-Binding Proteins tool transcription factor vascular smooth muscle cell proliferation vector wortmannin

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to investigate the mechanisms by which insulin signaling effects changes in cellular responses of vascular tissue to other more potent mitogens. We have recently shown that insulin augments the actions of PDGF and VEGF in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we would like to determine these mechanisms of cross-talk within these cells, determine molecular targets for therapeutic drugs and contribute to the understanding of the pathophysiology of vascular disease in diabetes. We hypothesize that hyperinsulinemia in the state of metabolic insulin resistance, augments the effects of more potent mitogens on the vasculature via increases in prenyltransferase activity, thereby increasing the amounts of prenylated Ras and Rho proteins that are available for mitogen-stimulated GTPloading, resulting in exaggerated cellular responses that lead to the development and progression of atherosclerosis. We will test this hypothesis using two important tools: (1) a dominant-negative mutant of the alpha-subunit (DNFTa) of farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) to help determine the mechanisms that link the insuring signaling pathway to other growth factor pathways, and (2) a tetracyline-inducible system to determine what effects does the expression of DNFTa in stably transfected vascular smooth muscle cells have upon insulin-stimulation of the Erk5 pathway. To determine these mechanisms we have defined three major Specific Aims: (1) Does DNFTa inhibit hyperinsulinemia's ability to potentiate the mitogenic effects of other growth factors in rat aorta vascular smooth muscle cells RASMC in the presence of insulin resistance; (2) Does DNFTa inhibit hyperinsulinemia's ability to potentiate the mitogenic effects of other growth factors in rat pulmonary aortic vascular endothelial cells PAVEC in the presence of insulin resistance; and (3) Does DNFTa inhibit insulin-stimulated phosphorylation, activation and translocation of Erk5 in RASMC in the presence of insulin resistance.

描述（由申请人提供）：我们的长期目标是研究胰岛素信号传导影响血管组织对其他更有效的有促促是有效的有促促是细胞反应的变化的机制。我们最近表明，胰岛素增强了PDGF和VEGF在血管平滑肌细胞（VSMC）和内皮细胞（EC）中的作用。因此，我们想确定这些细胞中交叉对话的这些机制，确定治疗药物的分子靶标，并有助于理解糖尿病中血管疾病的病理生理学。 We hypothesize that hyperinsulinemia in the state of metabolic insulin resistance, augments the effects of more potent mitogens on the vasculature via increases in prenyltransferase activity, thereby increasing the amounts of prenylated Ras and Rho proteins that are available for mitogen-stimulated GTPloading, resulting in exaggerated cellular responses that lead to the development and progression of atherosclerosis. We will test this hypothesis using two important tools: (1) a dominant-negative mutant of the alpha-subunit (DNFTa) of farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I) to help determine the mechanisms that link the insuring signaling pathway to other growth factor pathways, and (2) a tetracyline-inducible system to determine what effects does the expression of ERK5途径的胰岛素刺激后，稳定转染的血管平滑肌细胞中的DNFTA具有。为了确定这些机制，我们定义了三个主要的特定目的：（1）DNFTA是否会抑制高胰岛素血症在胰岛素抵抗的情况下增强其他生长因子在大鼠主动脉血管平滑肌细胞RASMC中的有丝分裂作用的能力；（2）DNFTA是否会抑制高胰岛素血症在胰岛素抵抗存在下PAVEC中大鼠肺主动脉血管内皮细胞PAVEC增强其他生长因子的有丝分裂作用的能力；（3）DNFTA会抑制胰岛素抗胰岛素耐药性的胰岛素刺激的磷酸化，ERK5的激活和易位。