Vascular Dysfunction in Myocardial Ischemia and metabolic Syndrome

 描述(申请人提供)：糖尿病和相关心血管并发症的患病率在全球范围内急剧增加。与非糖尿病患者相比，患有糖尿病和糖耐量异常的患者发生心血管事件的风险高达8倍，而心血管疾病是这一人群死亡的最大原因。尽管糖尿病患者血管功能异常的分子机制已经在体外和啮齿动物模型中得到了检验，但它们在侧支血管形成中的确切作用仍不清楚。在对大型动物和患者的研究中，缺乏对这些概念的验证和推广。这一理解是将其应用于人类的基本前提。我们将在高脂饲料喂养的约克郡猪中诱导胰岛素抵抗，创建一个模型，重建糖尿病患者存在的许多代谢、分子和微循环异常。我们先前的研究和初步数据表明，猪糖尿病模型与患者的疾病非常相似，并导致心肌和血管再生减少，我们将在本提案中使用该模型。我们的重点是侧支依赖血流、血管密度和微血管功能的功能变化，以及体内侧支形成过程中涉及的关键分子事件。我们将使用机械论的方法来了解通路和网络中的分子相互作用以及功能属性，以揭示糖尿病血管生成受损的分子基础。我们已发表的初步数据表明，己糖胺生物合成途径(HBP)、蛋白质O-GlcN酰化和胰岛素信号转导中可能存在参与和功能相互作用。建议的综合方法将导致在促血管生成治疗、基于细胞的再生和组织工程中的关键途径、分子靶点和策略的确定，这一建议的临床重要性是显而易见的。使用患有2型糖尿病和代谢综合征的大型动物模型是该项目的一个重要方面。

 DESCRIPTION (provided by applicant): The prevalence of diabetes and related cardiovascular complications is dramatically increasing worldwide. Patients with diabetes and glucose intolerance carry up to eight times the risk of cardiovascular events compared to nondiabetic individuals and cardiovascular disease is the largest cause of mortality in this population. Although the molecular mechanisms that underlie the abnormal vascular function in diabetic conditions have been examined in in-vitro and in rodent models, their exact role in collateral vessel formation are largely unknown. The validation and extension of these concepts in studies with large animals and patients is lacking. This understanding is an essential prerequisite to their application in humans. We will induce insulin resistance in Yorkshire pigs with high fat feeding creating a model that recreates many of the metabolic, molecular, and microcirculatory abnormalities present in diabetic patients. Our prior studies and preliminary data show that porcine models of diabetes closely resemble the disease in patients and lead to diminish myocardial and vascular regeneration and we will use the model in this proposal. Our focus is on functional changes in collateral dependent flow, vascular density, and microvascular function together with key molecular events involved in the altered collateral formation process in vivo. We will use mechanistic approach to understand molecular interactions in pathways and networks and functional attributes to unravel the molecular base of impaired angiogenesis in diabetes. Our published and preliminary data suggests for involvement and functional interactions in the hexosamine biosynthetic pathway (HBP), protein O- GlcNAcylation, and insulin signaling. The proposed integrated approach will result in the identification of crucial pathways, molecular targets, and strategies in pro-angiogenic therapy and cell based regeneration and tissue engineering, the clinical importance of this proposal is evident. The use of a large animal model with type 2 diabetes and metabolic syndrome is a strong aspect of the project.