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

• 批准号: 10586048
• 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
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586048
• 关键词: Acute; Address; Adhesions; Affect; Aorta; Apoptotic; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Blood; Blood Circulation; 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 Progression; 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; Leukocytes; Ligation; Link; Lipids; Low Density Lipoprotein Receptor; LoxP-flanked allele; Macrophage; 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; Transfection; Vascular Diseases; Vascular Endothelial Cell; Vascular Permeabilities; Western Blotting; aortic arch; ascending aorta; conditional knockout; endothelial dysfunction; gain of function; hemodynamics; innovation; loss of function; 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

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.

项目摘要/摘要 流动血会产生一种称为剪切应力的摩擦力，在内皮中起着重要作用 功能障碍和动脉粥样硬化。动脉的分支和弯曲暴露于低和干扰的流​​动（D-Flow）， 一种促进血管功能障碍和动脉粥样硬化的机械环境。相反，在生理上 稳定层流（S-Flow）产生的高剪切应力是保护性的。螺旋流（H-Flow）与 高级剪切应力不仅存在于升主动脉中，而且还存在于其他部位（例如冠状动脉） 动脉，降主动脉，常见动脉和普通股动脉。 h-flow可能有几个积极的 生理角色，例如抑制/消除流量停滞的区域，阻止了 动脉腔表面上的动脉粥样硬化脂质，并增强从血液到血液的氧气转运 动脉壁。内皮细胞（EC）是导致动脉粥样硬化的剪切应力的临界传感器。 肾上腺细胞增多症是一个过程，通过吞噬细胞吞噬凋亡组织，例如 专业的吞噬细胞（例如巨噬细胞和未成熟的树突状细胞）和非专业吞噬细胞 （例如，ECS，上皮细胞，成纤维细胞和一些基质细胞）。巨噬细胞中有缺陷的肿瘤病促进 高级动脉粥样硬化。但是，剪切应力环境调节EC的机制 肿瘤病及其在动脉粥样硬化中的影响仍然很大未知。要测试的中央假设 在这个项目中，血流模式调节EC的传染性吞噬作用和随后的内皮功能障碍和 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 流动模式和EC传染性细胞增多症及其在动脉粥样硬化发展中的作用。我们的具体目标是目标 1-定义血液流动模式在EC肿瘤病和内皮功能障碍中的作用，AIM 2-确定 MERTK在内皮机械传输中的作用，目标3-评估EC传染性细胞增多症的贡献 动脉粥样硬化。为了靶向内皮，必须定义肾上细胞增多症调节的机制 机械转导和随后的内皮功能障碍。拟议的研究在某种意义上是创新的 我们将连接血流模式，EC传染性细胞增多症和内皮机械转导。我们也会 评估EC肿瘤病的新型机制及其对动脉粥样硬化的贡献。