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

基本信息

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
项目类别：
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

项目摘要

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）是普通人群心血管疾病的独立危险因素，并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 HHcy 时，心血管死亡率比没有 HHcy 的糖尿病患者高约 2 倍。我们已经获得了大量的初步数据，表明HHcy和高血糖（HHcy/HG）的组合加速了动脉粥样硬化病变的发展，病变中单核细胞（MC）/巨噬细胞（MØ）增加，MC和MØ的炎症亚群升高（Ly6Cmiddle+高）外周组织中的 MC 和 M1 MØ）众所周知，炎症性 MC 和 MØ 会导致血管和全身炎症。检查 Hcy 在 MC/MØ 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 和糖尿病的组合疾病中，我们的中心假设是 HHcy 通过 DNA 低甲基化促进炎症 MC/MØ 分化。我们将通过以下三个目标来检验我们的假设：目标 1 将检查 HHcy 对炎症 MC/MØ 分化的影响。目标 2 将了解 T2DM 中 HHcy 诱导的 MC 分化的机制，目标 3 将确定 DNA 低甲基化在介导 HHcy 诱导的 MC 分化中的作用，并测试一种新的 DNA 甲基化疗法在预防炎症性 MC/ 中的作用。糖尿病动物的 MØ 分化和血管疾病。该项目的成功将促进 HHcy 相关糖尿病心血管疾病的新疗法的开发。