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: 8419884
• 负责人: Xiaofeng Yang
• 金额: $ 36.41万
• 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/8419884
• 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，hcy在血管炎症和动脉粥样硬化中的作用的生化机制尚不明确。大多数免疫细胞促进炎症，而CD4+CD25highFoxp3+调节性T细胞（Tregs）是最有效的免疫抑制细胞，可抑制血管炎症。Tregs，而不是其他T细胞，在同型半胱氨酸（Hcy）升高-载脂蛋白E缺乏（ApoE-/-）小鼠中减少。因此，HHcy促进Treg的减少可能会削弱免疫抑制，加速血管炎症。本项目的目的是验证我们的中心假设，即HHcy导致Treg中DNA甲基化抑制，从而导致Treg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。该项目是基于王宏博士（合作研究者）实验室的开创性发现，即HHcy促进半胱硫氨酸-合成酶(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会导致SAH （s -腺苷型同型半胱氨酸，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）和动脉中的Treg凋亡（表型研究）。(2)确定hhcy诱导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和HHcy对Treg和Treg细胞凋亡中Bax表达的致病作用（治疗/抑制研究）。这个项目的成功意义重大，可能会导致