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Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension

既定高血压中的基质相互作用分子 1、免疫细胞和血管病理学

基本信息

批准号：
10455479
负责人：
KHALID MATROUGUI
金额：
$ 37.5万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455479
关键词：
Address Adverse event Angiotensins Anti-Inflammatory Agents Apoptosis Biological Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Communication Cell Count Cell Death Cell membrane Cell physiology Cells Chimera organism Clinical Clip Complication Cytokine Signaling Data Dendritic Cells Dendritic cell activation Development Endoplasmic Reticulum Endothelial Cells Female Fibrosis Generations Genotype Goals Hypertension IL2RA gene Immune Immune system Inflammation Inflammatory Infusion procedures Interferon Type II Interleukin-1 beta Kidney Knockout Mice Mediator of activation protein Menopause Mission Modeling Molecular Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Outcome Ovariectomy Pathologic Processes Pathology Patients Preventive Proteins Public Health Regulatory T-Lymphocyte Reporting Research Priority STIM1 gene Ships Signal Transduction Strategic Planning Structure T-Lymphocyte Tail Testing Therapeutic Translational Research Translations Vascular Diseases Vascular Endothelium Vascular System base blood pressure elevation calcification cardiovascular risk factor clinically significant cytokine design endoplasmic reticulum stress endothelial dysfunction gene therapy high risk hypertensive improved male mortality mouse model multidisciplinary novel therapeutics overexpression prevent therapy resistant

项目摘要

ABSTRACT — The central mechanisms involved in hypertension-induced vascular pathology, a public health crisis, remain unknown. There is still a significant rate of adverse events in hypertensive patients prescribed these therapeutic and 2/3 of hypertensive patients are still resistant to these therapies. Thus, the critical unmet need is to identify mechanism based-treatable targets to rescue vascular function and structure in established hypertension. The pilot data showed that transferring healthy Treg into a mouse with established hypertension-induced by angiotensin II (Ang II) infusion improved vascular endothelial function and structure. We showed an increase in stromal interaction molecule 1 (STIM1) expression in Treg that could be responsible for Treg apoptosis by Nox2 and endoplasmic reticulum (ER) stress- dependent mechanisms. The overexpression of STIM1 in Treg cell caused Treg cell apoptosis. The depletion of dendritic cells in hypertensive mice improved arterial function and reduced arterial fibrosis and calcification through a reduction in INFγ and IL-1β release from dendritic cells and the inhibition of the ER stress in the endothelial cells. The central hypothesis is that STIM1 overexpression in Treg cells, through ROS and ER stress mechanism, cause Treg cells apoptosis and decrease IL-10 release, which increases dendritic cell activity leading to an increase in pro-inflammatory cytokines release (INFγ and IL-1β) and a decrease in anti-inflammatory IL-10 release causing the induction of the ER stress in endothelial cells and vascular pathology. To advance the Translational Sciences, we will test the hypothesis in two-kidney one- clip (2K1C) hypertensive mice Ang II-dependent. Specific Aim #1: To determine that in established hypertension, STIM1 expression is increased in Treg cells causing Treg cells apoptosis, a decrease in IL-10 release, and vascular pathology. Thus disrupting STIM1 expression in Treg cells would restore Treg cells number, IL-10 levels, and improve vascular endothelial function and reduce fibrosis and calcification in established hypertension. Specific Aim #2: To delineate that the decrease in IL-10 release, because of apoptosis in Treg, increases dendritic cells activity to release IFNγ and IL-1β and blunt IL-10 release, which causes vascular pathology via the induction of the ER stress mechanism in endothelial cells, and therefore depleting dendritic cells or manipulating the ER stress in endothelial cell improve vascular endothelial function and reduce fibrosis and calcification in established hypertension-induced by 2K1C. These studies are central to the mission of the NHLBI and address all Goals and multiple Strategies outlined in the NHLBI Strategic Plan. These studies will address 1) a need to further illuminate the biological mechanisms and pathological processes of the contribution of the immune cells, 2) The interaction between the immune system and the vascular system as a priority research topic and, 3) To advance the Translational Sciences, we will test the hypothesis in 2K1C mice model.

摘要：高血压引起的血管病理的中心机制