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ARGINASE AND ARTERIAL INJURY

精氨酸酶和动脉损伤

基本信息

批准号：
7576180
负责人：
WILLIAM DURANTE
金额：
$ 31.36万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
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：
2005-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576180
关键词：
Adenoviruses Animal Model Apoptosis Arginine Arterial Injury Arteries Attenuated Biological Blood Vessels Carotid Arteries Carotid Artery Injuries Cell Cycle Proteins Cell Proliferation Cell physiology Characteristics Collagen Data Disease Drug or chemical Tissue Distribution Endothelial Cells Enzymes Exhibits Functional disorder Gene Deletion Gene Expression Gene Transfer Genes Genetic Growth Factor Hepatic Homocysteine Homocystine Hyperhomocysteinemia In Vitro Infection Inflammation Inflammatory Injury Investigation Laboratories Link Mediating Mitogens Modeling Mus Nitric Oxide Ornithine Pilot Projects Play Polyamines Process Production Proline Protein Isoforms Rattus Regulation Research Proposals Role Site Smooth Muscle Myocytes Stimulus Testing Urea Vascular remodeling Vasodilation arginase base cell growth cytokine hemodynamics in vivo Model migration new therapeutic target novel overexpression prevent proline-nitric oxide research study response response to injury urea cycle vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): The broad long-term objective of this research proposal is to establish arginase I as a novel regulator of vascular function. We have discovered that vascular smooth muscle cells (SMC) express arginase I and that vascular mitogens and atherogenic factors found at sites of vascular injury stimulate arginase I gene expression. The central hypothesis of this proposal is that arginase I is a critical regulator of the SMC response to vascular injury. To test our hypothesis, we plan to pursue the following 3 complementary and linked specific aims. In aim 1, the effect of arginase on vascular SMC proliferation, migration, collagen and nitric oxide (NO) synthesis will be investigated. If arginase I stimulates SMC growth, migration, or collagen synthesis we will determine whether polyamines or L-proline mediate these actions. In addition, the effect of arginase I on cell cycle proteins will be explored. In contrast, if arginase I inhibits inflammatory cytokine-mediated NO production we will examine if this is mediated via the depletion of intracellular L-arginine. We will also determine if the inhibition of NO formation by arginase I prevents SMC apoptosis. In aim 2, the regulation and role of arginase I on the response to arterial injury will be investigated. These studies will examine the expression of arginase I as well as the production of polyamines, L-proline, and NO using the rat carotid artery injury model. We will also determine whether inhibition of arginase I activity using pharmacological and antisense approaches attenuates the remodeling response following arterial injury. Alternatively, we will examine whether arginase I gene transfer to the vessel wall exacerbates the remodeling response. In addition, we will generate mice with homozygous arginase I inactivation targeted specifically to vascular SMC and determine whether this influences the remodeling response. In aim 3, the regulation and role of arginase I in hyperhomocysteinemia will be investigated using cultured SMC and genetic and dietary animal models of hyperhomocysteinemia. It is anticipated that this project will (a) establish arginase I as a novel regulator of the vessel wall's response to injury and (b) implicate the arginase I enzyme as a promising new therapeutic target in treating atheroproliferative disorders of the vessel wall.

描述（由申请人提供）：本研究提案的广泛长期目标是将DAPINASE I确立为血管功能的新型调节剂。我们发现血管平滑肌细胞（SMC）表达β-淀粉样蛋白酶I，并且在血管损伤部位发现的血管有丝分裂原和致动脉粥样硬化因子刺激β-淀粉样蛋白酶I基因表达。该建议的中心假设是，β-淀粉酶I是SMC对血管损伤反应的关键调节剂。为了验证我们的假设，我们计划追求以下3个互补和相关的具体目标。目的1：研究胰蛋白酶对血管平滑肌细胞增殖、迁移、胶原和一氧化氮（NO）合成的影响。如果腺苷酸酶I刺激SMC生长、迁移或胶原合成，我们将确定是否多胺或L-脯氨酸介导这些作用。此外，还将探讨酶I对细胞周期蛋白的影响。相反，如果辅酶I抑制炎性精氨酸介导的NO产生，我们将检查这是否是通过细胞内L-精氨酸的消耗介导的。我们还将确定是否抑制NO的形成，由辅酶I阻止SMC凋亡。在目标2中，将研究乙酰胆碱酯酶I对动脉损伤反应的调节和作用。这些研究将使用大鼠颈动脉损伤模型来检测多胺酶I的表达以及多胺、L-脯氨酸和NO的产生。我们还将确定是否使用药理学和反义方法抑制血管生成酶I活性减弱动脉损伤后的重塑反应。或者，我们将研究是否转移到血管壁的β-淀粉酶I基因加重重塑反应。此外，我们将产生专门针对血管平滑肌细胞的纯合型α-淀粉酶I失活小鼠，并确定这是否影响重塑反应。目的3：利用培养的平滑肌细胞和高同型半胱氨酸血症的遗传和饮食动物模型，研究高同型半胱氨酸血症中胰蛋白酶I的调节和作用。预期该项目将（a）确立作为血管壁对损伤的反应的新型调节剂的酶I，和（B）暗示酶I作为治疗血管壁的动脉粥样硬化增生性疾病的有前景的新治疗靶点。