HHcy-induced Inflammatory Monocyte and Macrophage Differentiation in Diabetes

 说明(申请人提供)：高同型半胱氨酸血症(HHcy)是普通人群心血管疾病的独立危险因素，与糖尿病患者的血管疾病有关[Hackam，2003#101；Schnyder，2002#102；Schnyder，2002#102}。当糖尿病合并同型半胱氨酸时，心血管死亡率大约是非同型半胱氨酸者的两倍。我们已经获得了大量的初步数据，表明HHcy和高血糖(HHcy/HG)的结合加速了动脉粥样硬化病变的发展，病变内单核细胞(MC)/巨噬细胞(M？)增加，外周组织中MC和M？(Ly6C中+高MC和M1 M？)炎性亚群增加。已知炎性MC和M？参与血管和全身炎症。在这个提案中，我们将研究Hcy在MC/M？分化和血管炎症中的作用和机制，血管炎症是决定动脉粥样硬化和心血管疾病的关键状态，在HHcy和糖尿病的组合性疾病中。我们的中心假设是HHcy通过DNA低甲基化促进炎性MC/M？分化，从而加速糖尿病动脉粥样硬化的形成。我们将通过以下三个目标来验证我们的假设：目标1将检测HHcy对糖尿病动物炎性MC/M？分化和血管疾病的影响。目的探讨同型半胱氨酸诱导2型糖尿病MC分化的机制。目的研究DNA低甲基化在高同型半胱氨酸诱导的MC分化中的作用，并探索一种新的DNA甲基化治疗方法，以预防糖尿病动物的炎性MC/M？分化和血管病变。该项目的成功将导致HHcy相关糖尿病心血管疾病的新疗法的开发。

 DESCRIPTION (provided by applicant): Hyperhomocycteinemia (HHcy) is an independent risk factor for cardiovascular disease in the general population and associated with vascular diseases in diabetic patients{Hackam, 2003 #101;Schnyder, 2002 #102;Schnyder, 2002 #102}. When diabetes is compounded HHcy, cardiovascular mortality is about 2-fold greater than in those without HHcy. We have obtained substantial preliminary data showing that the combination of HHcy and Hyperglycemia (HHcy/HG) accelerated the development of atherosclerotic lesion, increased monocyte (MC)/macrophage (MØ) in the lesion, elevated inflammatory subsets of MC and MØ (Ly6Cmiddle+high MC and M1 MØ) in peripheral tissues. It is known that inflammatory MC and MØ contribute to vascular and systemic inflammation. In this proposal, we will examine the role and mechanism of Hcy in MC/MØ differentiation and in vascular inflammation, a key status determining atherosclerosis and cardiovascular disease, in combinatory diseases of HHcy and diabetes. Our central hypothesis is that HHcy promotes inflammatory MC/MØ differentiation via DNA hypomethylation thereby accelerating atherogenesis in diabetes. We will test our hypothesis by using the following three Aims: Aim 1 will examine the effect of HHcy on inflammatory MC/MØ differentiation and vascular diseases in diabetes animals. Aim 2 will access mechanisms contributing to HHcy-induced MC differentiation in T2DM. Aim 3 will identify the role of DNA hypomethylation in mediating HHcy- induced MC differentiation and test a novel DNA methylation therapy in preventing inflammatory MC/MØ differentiation and vascular diseases in diabetes animals. Success of this project will lead to the development of novel therapeutics for HHcy- related diabetic cardiovascular disease.