HHcy-induced Bax upregulation, Treg apoptosis and vascular disease

描述（由申请人提供）：血浆同型半胱氨酸（Hcy）水平升高，称为高同型半胱氨酸血症（HHcy），是人类冠心病（CHD）和卒中的独立危险因素。 然而，高同型半胱氨酸在血管炎症和动脉粥样硬化中的作用的生化机制尚不清楚。 大多数免疫细胞促进炎症，而CD 4 + CD 25 highFoxp 3+调节性T细胞（TcM），最有效的免疫抑制细胞，抑制血管炎症。 在同型半胱氨酸（Hcy）升高的载脂蛋白E缺陷（ApoE-/-）小鼠中，T细胞减少，但其他T细胞没有减少。 因此，HHcy促进的Treg减少可减弱免疫抑制并加速血管炎症。本项目的目标是检验我们的中心假设，即HHcy导致Tcells中DNA甲基化的抑制，这导致Tcells中促凋亡蛋白Bax的上调和激活，并增加Treg凋亡，最终导致血管炎症和功能障碍增加。该项目是基于Hong Wang博士（共同研究者）实验室的开创性发现提出的，即HHcy促进胱硫醚合酶（Cbs）-/-/ApoE-/-双敲除（KO）小鼠的血管炎症和动脉粥样硬化。 Wang的团队也是第一个证明HHcy导致SAH（S-腺苷高半胱氨酸，一种有效的甲基转移酶抑制剂）和DNA低甲基化的积累。 此外，我们的实验室在表征血管炎和血管炎症中的细胞凋亡途径方面具有长期的兴趣和出版记录。我们的目标将通过执行以下具体目标来实现：（1）表征HHcy小鼠中脾脏、骨髓（BM）、外周血（PB）和动脉中的Treg凋亡（表型研究）。(2)确定HHcy诱导的Treg细胞凋亡和血管炎症的潜在机制（机制研究）。 (3)确定DNA低甲基化的介导作用和HHcy对TcB和Treg细胞凋亡中Bax表达的致因作用（治疗/抑制研究）。该项目的成功意义重大，可能会导致 本发明涉及开发抑制HHcy诱导的Treg细胞凋亡和增强Treg对HHcy诱导的血管炎症的抑制的新治疗方法。

DESCRIPTION (provided by applicant): Elevated level of plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), is an independent risk factor for human coronary heart disease (CHD) and stroke. However, the biochemical mechanisms underlying the effects of HHcy in vascular inflammation and atherosclerosis are poorly defined. The majority of immune cells promote inflammation whereas CD4+CD25highFoxp3+ regulatory T cells (Tregs), the most potent immuno-suppressive cells, inhibit vascular inflammation. Tregs, but not other T cells, are decreased in homocysteine (Hcy) elevated-apolipoprotein E deficient (ApoE-/-) mice. Consequently, HHcy- promoted Treg reduction may weaken immune suppression and accelerate vascular inflammation. The goal of this project is to examine our central hypothesis that HHcy causes the suppression of DNA methylation in Tregs, which leads to upregulation and activation of pro-apoptotic protein Bax in Tregs and increased Treg apoptosis, and finally contribute to increased vascular inflammation and dysfunction. This project is proposed based on the pioneer findings from Dr. Hong Wang (co-investigator)'s laboratory that HHcy promotes vascular inflammation and atherosclerosis in cystathionine ¿-synthase (Cbs)-/-/ApoE-/- double knock-out (KO) mice. Wang's team was also the first to show that HHcy leads to accumulation of SAH (S-adenosylhomocysteine, a potent inhibitor of methyltransferases) and DNA hypomethylation. In addition, our laboratory has a long- standing interest and publication record in characterizing apoptosis pathways in Tregs and vascular inflammation. Our goal will be pursued through the execution of the following specific aims: (1) Characterize Treg apoptosis in the spleen, bone marrow (BM), peripheral blood (PB), and arteries in HHcy mice (phenotypic studies). (2) Determine the mechanisms underlying HHcy-induced Treg apoptosis and vascular inflammation (mechanistic studies). (3) Determine the mediating role of DNA hypomethylation and the causative role of HHcy on Bax expression in Tregs and Treg apoptosis (therapeutic/inhibitory studies). Success of this project is significant, which may lead to the development of new therapeutic approaches to inhibit HHcy-induced Treg apoptosis and enhance Treg suppression of HHcy-induced vascular inflammation.