Macrovascular Dysfunction of Diabetes

糖尿病大血管功能障碍

• 批准号: 7021466
• 负责人: MARC Lee GOALSTONE
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021466
• 关键词: alkyltransferase; diabetic angiopathy; enzyme activity; enzyme induction /repression; enzyme mechanism; enzyme structure; guanine nucleotide binding protein; hormone regulation /control mechanism; hyperinsulinism; insulin; insulin sensitivity /resistance; platelet derived growth factor; prenylation; protein engineering; tissue /cell culture; vascular endothelial growth factors; vascular endothelium; vascular smooth muscle

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。