HHcy-induced Inflammatory Monocyte and Macrophage Differentiation in Diabetes

HHcy 诱导的糖尿病炎症单核细胞和巨噬细胞分化

• 批准号: 8969420
• 负责人: Hong Wang
• 金额: $ 44.33万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-20 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969420
• 关键词: Accounting; Adult; Affect; Animals; Area; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biological Models; Blood Vessels; Bone Marrow; Bone Marrow Cells; Cardiovascular Diseases; Cardiovascular system; Child; Cystathionine; DNA; DNA Methylation; DNA Modification Methylases; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Diet; Disease; Disease model; Flow Cytometry; General Population; Genes; Genome; Glucose; High Prevalence; Homocysteine; Homocystine; Human; Hyperglycemia; Hyperhomocysteinemia; Hyperlipidemia; ITGAM gene; Inflammation; Inflammatory; Injection of therapeutic agent; Insulin; Lead; Lesion; Liver; Mediating; Metabolic; Metabolic Diseases; Methionine; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Primary Cell Cultures; Reporting; Risk Factors; Role; S-Adenosylhomocysteine; Shotguns; Smoking; Spleen; Splenocyte; Streptozocin; Subfamily lentivirinae; Testing; Tissues; Transcriptional Regulation; Transplantation; Vascular Diseases; atherogenesis; bisulfite sequencing; cardiovascular disorder risk; db/db mouse; diabetic; diabetic cardiomyopathy; diabetic patient; in vitro Model; insight; knockout gene; macrophage; monocyte; mortality; mouse model; new therapeutic target; novel; novel therapeutics; prevent; public health relevance; success; vascular inflammation

 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.

 描述（由申请人提供）：高同型半胱氨酸血症（HHcy）是一般人群心血管疾病的独立风险因素，与糖尿病患者的血管疾病相关{Hackam，2003 #101;Schnyder，2002 #102;Schnyder，2002 #102}。当糖尿病合并高同型半胱氨酸时，心血管疾病死亡率比不合并高同型半胱氨酸的患者高2倍。我们已经获得大量的初步数据表明，HHcy/HG联合应用加速了动脉粥样硬化病变的发展，增加了病变中的单核细胞（MC）/巨噬细胞（M1），增加了外周组织中MC和M1的炎性亚群（Ly 6C中+高MC和M1 M1）。众所周知，炎性MC和MMPs有助于血管和全身炎症。在本研究中，我们将探讨同型半胱氨酸在MC/MC分化和血管炎症中的作用和机制，这是决定动脉粥样硬化和心血管疾病的关键状态，在同型半胱氨酸和糖尿病的组合疾病中。我们的中心假设是HHcy通过DNA低甲基化促进炎性MC/MCs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的来验证我们的假设：目的1将检查HHcy对糖尿病动物的炎性MC/MC分化和血管疾病的影响。目的2探讨同型半胱氨酸诱导2型糖尿病MC分化的机制。目的3：探讨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甲基化治疗方法来预防糖尿病动物的MC/MC分化和血管病变。该项目的成功将导致开发新的治疗高同型半胱氨酸相关的糖尿病心血管疾病的药物。