NADHP Oxidase-mediated MC differentiation & Endothelial Dysfunction in HHcy

描述（由申请人提供）：新申请的总体目标是确定nadph相关氧化应激在高同型半胱氨酸血症（HHcy）引起的单核细胞分化和内皮功能障碍中的作用和机制。本文拟验证的假设是：HHcy引起SAH积累，导致NADPH氧化酶基因发生低甲基化表观遗传修饰，导致NADPH氧化酶相关的氧化应激和炎性MC分化，导致血管功能障碍。本项目将利用三个相关的具体目标来研究这一假设。在Aim 1中，他们将表征HHcy小鼠的MC分化/粘附和血管功能/炎症。在Aim 2中，他们将研究NADPH氧化酶激活和表观遗传修饰在hcy诱导的小鼠原发性脾细胞MC分化中的作用和机制。在Aim 3中，他们将确定HHcy、SAH积累、DNA低甲基化和NADPH氧化酶激活在Tg-hCBS Cbs-/-小鼠炎症性MC分化和血管功能障碍中的作用。我们相信，完成这一提议的具体目标可能为Hcy在CVD中的作用提供重要的见解，并确定其潜在的机制。

DESCRIPTION (provided by applicant): The overall objective of new application is to determine the role and mechanism of NADPH-related oxidative stress in Hyperhomocysteinemia (HHcy)-caused monocyte differentiation and endothelial dysfunction. The hypothesis to be tested in this proposal is that HHcy causes SAH accumulation, resulting in hypomethylative epigenetic modification on NADHP oxidase gene, leading to NADPH oxidase-related oxidative stress and inflammatory MC differentiation, contributing to vascular dysfunction. This project will study this hypothesis utilizing three linked specific aims. In Aim 1, they will characterize MC differentiation/adhesion, and vascular function/inflammation in HHcy mice. In Aim 2, they will examine the role and mechanism of NADPH oxidase activation and epigenetic modification in Hcy-induced MC differentiation in mouse primary splenocytes. In Aim 3, they will define the role of HHcy, SAH accumulation, DNA hypomethylation, and NADPH oxidase activation in inflammatory MC differentiation and vascular dysfunction in Tg-hCBS Cbs-/- mice. It is believed that completion of the specific aims of this proposal may provide important insights into the role of Hcy in CVD, and identify the underline mechanism. PUBLIC HEALTH RELEVANCE: Increased plasma homocysteine (Hcy) level is an independent risk factor for cardiovascular diseases (CVD). However, the underlying mechanism is largely unknown. This project will illustrate mechanism by which how Hcy causes vessel wall inflammation and impair vascular function, both are early events of cardiovascular disease. We anticipate this study will identify biomarker and novel therapeutic target of cardiovascular disease.