Impact of hemodynamics on efferocytosis in endothelial cells

血流动力学对内皮细胞胞吞作用的影响

基本信息

批准号：
10416262
负责人：
Zufeng Ding
金额：
$ 34.2万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10416262
关键词：
Acute Address Adhesions Affect Apoptotic Area Arterial Fatty Streak Arteries Atherosclerosis Binding Blood Blood Vessels Blood flow CRISPR-mediated transcriptional activation CRISPR/Cas technology Cardiovascular system Cell Line Cells Cessation of life Chemicals Chronic Clinical Coagulation Process Common Femoral Artery Common iliac artery structure Complex Coronary artery Data Dendritic Cells Descending aorta Development Diet Disease Drug Design Endothelial Cells Endothelium Environment Epithelial Cells Event Exposure to Failure Fibrin Fibroblasts Flow Cytometry Friction Functional disorder Geometry Goals Growth High Fat Diet Human Impairment In Vitro Inflammation Knock-out Lead Leukocytes Ligation Link Lipids Low Density Lipoprotein Receptor Mechanics Mediating Mesenchymal Modeling Mus Myocardial Ischemia NADPH Oxidase Necrosis Pathogenesis Pattern Phagocytes Phenotype Physiological Plasmids Play Prevention Process Production Protein S Regulation Research Role Rotation Rupture Stroke Stromal Cells Surface Testing Tissues Vascular Diseases Vascular Endothelial Cell Vascular Permeabilities Western Blotting aortic arch ascending aorta base conditional knockout endothelial dysfunction hemodynamics innovation loss of function macrophage mechanical stimulus mechanotransduction member mouse model neutrophil cytosol factor 40K neutrophil cytosol factor 67K novel novel therapeutic intervention oxygen transport prevent receptor response sensor shear stress single-cell RNA sequencing thrombotic treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Flowing blood generates a frictional force called shear stress that plays an important role in endothelial dysfunction and atherosclerosis. Branches and bends of arteries are exposed to low and disturbed flow (d-flow), a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress generated from steady laminar flow (s-flow) is protective. Helical flow (h-flow) associated with advanced shear stress exists not only in the ascending aorta but also in other parts such as the right coronary artery, descending aorta, common iliac artery, and common femoral artery. H-flow may have several positive physiological roles, such as suppressing/eliminating areas of flow stagnation, preventing the accumulation of atherogenic lipids on the luminal surfaces of arteries, and enhancing oxygen transport from the blood to the arterial wall. Endothelial cells (ECs) are critical sensors of the shear stress that contributes to atherosclerosis. Efferocytosis is a process by which apoptotic tissue is recognized for engulfment by phagocytic cells, such as professional phagocytes (e.g., macrophages and immature dendritic cells) and non-professional phagocytes (e.g., ECs, epithelial cells, fibroblasts, and some stromal cells). Defective efferocytosis in macrophages promotes advanced atherosclerosis. However, the mechanisms by which shear stress environments regulate EC efferocytosis and its implications in atherosclerosis remain largely unknown. The central hypothesis to be tested in this project is that blood flow patterns regulate EC efferocytosis and subsequent endothelial dysfunction and contribute to the development of atherosclerosis. Our long-term goal is to dissect the relationship between blood flow patterns and EC efferocytosis and its role in the development of atherosclerosis. Our specific aims are Aim 1- Define the role of blood flow patterns in EC efferocytosis and endothelial dysfunction, Aim 2- Determine the role of MerTK in endothelial mechanotransduction, and Aim 3- Evaluate the contribution of EC efferocytosis in atherosclerosis. Defining the mechanisms of efferocytosis regulation will be necessary to target endothelial mechanotransduction and subsequent endothelial dysfunction. The proposed research is innovative in the sense that we will connect blood flow patterns, EC efferocytosis, and endothelial mechanotransduction. We will also evaluate the novel mechanism of EC efferocytosis and its contribution to atherosclerosis.

项目概要/摘要流动的血液产生一种称为剪切应力的摩擦力，在内皮细胞中发挥重要作用功能障碍和动脉粥样硬化。动脉的分支和弯曲处暴露于低且受干扰的血流（d-血流）中，促进血管功能障碍和动脉粥样硬化的机械环境。反之，生理上稳定层流（s 流）产生的高剪切应力具有保护作用。螺旋流（h 流）与高级剪应力不仅存在于升主动脉，也存在于其他部位，例如右冠状动脉动脉、降主动脉、髂总动脉和股总动脉。 H流可能有几个积极的作用生理作用，例如抑制/消除流动停滞区域，防止积聚动脉管腔表面的致动脉粥样硬化脂质，并增强氧气从血液到动脉的输送动脉壁。内皮细胞（EC）是导致动脉粥样硬化的剪切应力的关键传感器。胞吞作用是凋亡组织被吞噬细胞识别并吞噬的过程，例如专业吞噬细胞（例如巨噬细胞和未成熟树突状细胞）和非专业吞噬细胞（例如，EC、上皮细胞、成纤维细胞和一些基质细胞）。巨噬细胞的胞吞作用缺陷促进晚期动脉粥样硬化。然而，剪切应力环境调节 EC 的机制胞吞作用及其对动脉粥样硬化的影响仍然很大程度上未知。待检验的中心假设在这个项目中，血流模式调节 EC 胞吞作用和随后的内皮功能障碍，有助于动脉粥样硬化的发展。我们的长期目标是剖析血液之间的关系血流模式和 EC 胞吞作用及其在动脉粥样硬化发展中的作用。我们的具体目标是 Aim 1- 定义血流模式在 EC 胞吞作用和内皮功能障碍中的作用，目标 2- 确定 MerTK 在内皮机械转导中的作用，目标 3-评估 EC 胞吞作用在内皮细胞机械传导中的贡献动脉粥样硬化。定义胞吞作用调节机制对于靶向内皮细胞是必要的。机械传导和随后的内皮功能障碍。所提出的研究在某种意义上是创新的我们将把血流模式、EC 胞吞作用和内皮机械传导联系起来。我们也会评估 EC 胞吞作用的新机制及其对动脉粥样硬化的贡献。