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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：称为高型星型血症（HHCY）的血浆同型半胱氨酸（HCY）的升高是人类冠心病（CHD）和中风的独立危险因素。然而，HHCY在血管感染和动脉粥样硬化中影响的生化机制的定义很差。大多数免疫球促进了注射，而CD4+ CD25Highfoxp3+调节性T细胞（Tregs）是最有效的免疫抑制细胞，抑制血管感染。在同型半胱氨酸（HCY）升高 - 倍脂蛋白E缺乏症（APOE-/ - ）小鼠中，Tregs而非其他T细胞降低。因此，HHCY促进的Treg还原可能会弱抑制和加速血管感染。该项目的目的是检查我们的中心假设，即HHCY在Treg中引起DNA甲基化的抑制，这导致Tregs中促凋亡蛋白Bax的上调和激活并增加Treg凋亡，并最终导致血管感染和功能障碍的增加。该项目是基于Hong Wang博士（共同研究者）的实验室的先驱发现提出的，该发现HHCY促进了Cystathionine�-伴侣酶（CBS）（CBS） - / - /APOE-/ - / - / - / - 双敲门型（KO）小鼠的血管性感染和动脉粥样硬化。王的团队也是第一个表明HHCY导致SAH积累的团队（S-腺苷类药物半胱氨酸，一种潜在的甲基转移酶抑制剂）和DNA降压甲基化。此外，我们的实验室在表征Treg和血管感染的凋亡途径方面具有长期的兴趣和出版记录。我们的目标将通过以下执行来实现。具体目的：（1）表征脾脏，骨髓（BM），外周血（PB）和HHCY小鼠中的动脉中的Treg凋亡（表型研究）。（2）确定HHCY诱导的Treg凋亡和血管感染的机制（机械研究）。（3）确定DNA低甲基化的介导作用以及HCY在Tregs和Treg凋亡中BAX表达（治疗/抑制性研究）中的致病作用。这个项目的成功很重要，这可能会导致开发新的治疗方法来抑制HHCY诱导的Treg凋亡并增强对HHCY诱导的血管炎症的抑制。