HHcy-induced Bax upregulation, Treg apoptosis and vascular disease

HHcy 诱导的 Bax 上调、Treg 细胞凋亡和血管疾病

• 批准号: 8666810
• 负责人: Xiaofeng Yang
• 金额: $ 46.03万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666810
• 关键词: Accounting; Apolipoprotein E; Apoptosis; Arteries; Atherosclerosis; Autoimmune Process; Bax protein; Binding Proteins; Biochemical; Biological; Blood Pressure; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cells; Cessation of life; Cholesterol; Chronic; Collaborations; Coronary heart disease; Cystathionine; DNA; DNA Methylation; DNA Methyltransferase; DNA Methyltransferase Inhibitor; DNA Modification Methylases; Data; Development; Event; Functional disorder; Future; Genes; Goals; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Hyperlipidemia; Immune; Immunosuppression; Inflammation; Inflammatory; Knockout Mice; Laboratories; Lead; Link; Maps; Mediating; Methylation; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myocardial Infarction; Neonatal; Peripheral; Peripheral arterial disease; Plasma; Public Health; Publications; RNA; Regulatory T-Lymphocyte; Reporting; Research Personnel; Risk; Risk Factors; Role; S-Adenosylhomocysteine; Small Interfering RNA; Spleen; Stroke; Subarachnoid Hemorrhage; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenes; Transgenic Mice; Up-Regulation; Vascular Diseases; Viral Vector; Water; Zinc; base; chromatin immunoprecipitation; inhibitor/antagonist; interest; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; peripheral blood; prevent; pro-apoptotic protein; promoter; protein expression; public health relevance; success; vascular inflammation

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.

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）和中风的独立危险因素。 然而，HHcy 在血管炎症和动脉粥样硬化中作用的生化机制尚不清楚。 大多数免疫细胞会促进炎症，而 CD4+CD25highFoxp3+ 调节性 T 细胞 (Treg)（最有效的免疫抑制细胞）会抑制血管炎症。 在同型半胱氨酸 (Hcy) 升高的载脂蛋白 E 缺陷 (ApoE-/-) 小鼠中，Treg 细胞减少，但其他 T 细胞不减少。 因此，HHcy 促进的 Treg 减少可能会削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 会抑制 Tregs 中的 DNA 甲基化，从而导致 Tregs 中促凋亡蛋白 Bax 的上调和激活，增加 Treg 细胞凋亡，最终导致血管炎症和功能障碍增加。该项目是基于王红博士（共同研究员）实验室的开创性发现而提出的，即HHcy促进胱硫醚锝-合酶（Cbs）-/-/ApoE-/-双敲除（KO）小鼠的血管炎症和动脉粥样硬化。 Wang的团队还首次证明HHcy会导致SAH（S-腺苷高半胱氨酸，甲基转移酶的有效抑制剂）的积累和DNA低甲基化。 此外，我们的实验室在表征 Tregs 和血管炎症的细胞凋亡途径方面有着长期的兴趣和发表记录。我们的目标将通过执行以下具体目标来实现：(1) 表征 HHcy 小鼠脾脏、骨髓 (BM)、外周血 (PB) 和动脉中 Treg 细胞凋亡的特征（表型研究）。 (2)确定HHcy诱导的Treg细胞凋亡和血管炎症的机制（机制研究）。 (3)确定DNA低甲基化的介导作用以及HHcy对Tregs中Bax表达和Treg细胞凋亡的致病作用（治疗/抑制研究）。该项目的成功意义重大，可能会导致 开发新的治疗方法来抑制 HHcy 诱导的 Treg 细胞凋亡并增强 Treg 对 HHcy 诱导的血管炎症的抑制。