Novel Strategies for prevention of diabetic vascular dysfunction.

描述（由申请人提供）：2型糖尿病与肥胖和慢性炎症相关，是一个主要的公共卫生问题，由于血管并发症导致发病率和死亡率。在人们患上2型糖尿病之前，他们几乎总是有高于正常水平的“糖尿病前期”血糖水平，但没有高到足以被诊断为糖尿病。美国有7900万糖尿病前期患者。最近的研究表明，心脏和血管系统的长期损害发生在糖尿病前期。造成这种病理的机制尚不清楚。虽然氧化应激和炎症是关键因素，但抗氧化剂/抗炎剂治疗对疾病进展影响不大。先前的研究表明，血管内皮功能障碍发生在2型糖尿病发展之前的糖尿病前期患者。因此，有必要明确导致血管损伤的机制和代谢过程，并开发新的预防或逆转治疗方法。我们的跨学科专家团队将研究导致2型糖尿病血管并发症的关键途径和生物标志物。我们的工作假设是精氨酸酶和吲哚胺2,3-双加氧酶（IDO）活性的增加通过炎症细胞因子产生和氧化应激的正反馈循环导致血管内皮功能障碍和炎症损伤。我们将研究导致精氨酸酶和IDO激活、氧化剂和细胞因子产生、慢性亚临床炎症、血管功能障碍和组织损伤的潜在分子机制。我们将使用啮齿动物模型和转化实验方法来评估胰岛素抵抗和2型糖尿病前期的人类受试者、肥胖/ 2型糖尿病小鼠和培养细胞的血管和骨髓来源细胞的功能。此外，白细胞、循环骨髓源性细胞和精氨酸酶和IDO（活性/表达、底物和产物）的血浆水平将被评估与氧化剂和细胞因子产生的关系。我们的目标是为阻断疾病进展提供新的生物标志物和靶点的证据。

DESCRIPTION (provided by applicant): Type 2 diabetes associated with obesity and chronic inflammation is a major public health problem, which causes morbidity and death due to vascular complications. Before people develop type 2 diabetes, they almost always have "pre-diabetes" blood glucose levels that are higher than normal, but not high enough to be diagnosed as diabetes. There are 79 million pre-diabetics in the US. Recent studies show that long-term damage to the heart and vascular system occurs during pre-diabetes. Mechanisms responsible for this pathology are not understood. While oxidative stress and inflammation are key factors, treatment with antioxidants/anti-inflammatory agents has little effect on disease progression. Previous studies have demonstrated that vascular endothelial dysfunction occurs in pre-diabetic patients prior to development of type 2 diabetes. Thus, there is great need to define the mechanisms and metabolic processes that cause vascular injury and develop new therapies for prevention or reversal. Our expert interdisciplinary team will examine key pathways and biomarkers leading to vascular complications of type 2 diabetes. Our working hypothesis is that increased arginase and indoleamine 2,3-dioxygenase (IDO) activity cause vascular endothelial dysfunction and inflammatory injury by a positive feedback cycle of inflammatory cytokine production and oxidative stress. We will examine potential molecular mechanisms that lead to arginase and IDO activation, oxidant, and cytokine production, chronic subclinical inflammation, vascular dysfunction and tissue damage. We will use rodent models and translational experimental approaches to assess function of vascular and bone marrow derived cells in human subjects who are insulin resistant and pre-type 2 diabetic, in mice with obesity/type 2 diabetes, and in cultured cells. Additionally, leukocytes, circulating bone marrow-derived cells and plasma levels of arginase and IDO (activity/expression, substrate and products) will be assessed in relation to production of oxidants and cytokines. Our objective is to generate evidence of novel biomarkers and targets for interrupting disease progression. PUBLIC HEALTH RELEVANCE: Understanding the molecular mechanisms responsible for development of vascular disease in type 2 diabetes is necessary for successful treatment and prevention.