Ambient fine particulate matter and bone marrow stem cells

环境细颗粒物和骨髓干细胞

• 批准号: 9767135
• 负责人: ZHENGUO LIU
• 金额: $ 32.95万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767135
• 关键词: Acetylcysteine; Air Pollution; Animal Model; Animals; Antioxidants; Apoptosis; Atherosclerosis; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Caliber; Cardiovascular Diseases; Cardiovascular system; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Complex; Coronary Arteriosclerosis; Data; Development; Endothelium; Exhibits; Exposure to; Generations; Health; Human; Impairment; Injury; Label; Lead; Life; Link; Mediating; Mus; Natural regeneration; Oxidative Stress; Particulate Matter; Pathogenesis; Patients; Play; Population; Prevention; Process; Production; Public Health; Reactive Oxygen Species; Role; Source; Stem cells; Stroke; Structure; Testing; Vascular Diseases; angiogenesis; antioxidant enzyme; base; burden of illness; copper zinc superoxide dismutase; endothelial dysfunction; experimental study; extracellular; fine particles; glutathione peroxidase; mortality; neointima formation; novel; novel strategies; overexpression; particle; peripheral blood; prevent; public health relevance; stem cell population; superoxide dismutase 1; transplant model

 DESCRIPTION (provided by applicant): Ambient fine particulate matter (PM) is the key components for air pollution, and associated with significant mortality. The majority of the mortality following PM exposure is related to cardiovascular diseases. Endothelial progenitor cells (EPCs) are critical to maintaining the integrity and function of blood vessels with bone marrow as one of their main sources. PM exposure exhibits various deleterious effects on cardiovascular system, and significantly decreases the number and function of EPCs. However, the mechanism(s) for PM exposure- induced impairment of EPCs has not been fully understood. Recently, we observed that PM exposure significantly decreased the level of circulating EPCs s and the population of bone marrow stem cells (BMSCs) within the bone marrow in association with increased level of reactive oxygen species (ROS) formation in mice. When ROS production was blocked, PM-induced reduction of EPCs and BMSCs was effectively prevented. The present project was proposed to test the hypothesis that "PM exposure reduces the number and function of EPCs through oxidative stress-mediated reduction of BMSC population in bone marrow with reduced generation of EPCs from BMSCs". There are two specific aims: 1): to determine the effect of PM exposure on BMSCs and their endothelial differentiation; and 2): to define the role of oxidative stress in mediating the effect of PM exposure on BMSCs and their differentiation into EPCs. We will demonstrate that PM exposure leads to a significant reduction in the number and function of BMSCs in the bone marrow. We will determine if the decrease in the number of BMSCs is due to increased apoptosis or decreased proliferation. We will also conduct experiments using bone marrow transplantation (BMT) with eGFP-positive BMSCs to determine if PM exposure impairs the differentiation of BMScs into EPCs that may contribute to decreased number and function of EPCs in the setting of PM exposure. To determine if PM exposure could produce a similar effect on BMSCs as chronic air pollution, the experiments will be repeated using mice exposed to air pollution for up to 6 months. We will test whether PM-induced ROS production causes decreased number and function of BMSCs by blocking ROS production using either antioxidant N-acetylcysteine or concomitant overexpression of an antioxidant enzyme network of human copper/zinc superoxide dismutase (SOD) 1, extracellular SOD3, and glutathione peroxidase with decreased ROS formation. We will also use BMT model with eGFP-BMSCs to determine if PM-induced oxidative stress plays a critical role in the differentiation of BMSCs into EPCs. Experiments will be conducted to evaluate the role of ROS in the population of BMSCs and their differentiation into EPCs in the mice exposed to air pollution for up to 6 months. The data from this study will provide important and novel information on the mechanisms for the development of cardiovascular diseases in patients with PM exposure and air pollution, and help explore new approaches to preventing and treating cardiovascular diseases related to PM exposure. 1

 描述（由申请人提供）： 环境细颗粒物 (PM) 是空气污染的关键成分，与显着的死亡率相关。PM 暴露后的大部分死亡与心血管疾病有关。维持血管的完整性和功能，而骨髓是其主要来源之一。PM 暴露会对心血管系统产生多种有害影响，并显着降低 EPC 的数量和功能。 PM 暴露引起的 EPC 损伤的机制尚未完全清楚。最近，我们观察到 PM 暴露显着降低了循环 EPC 的水平以及骨髓内骨髓干细胞 (BMSC) 的数量。随着小鼠体内活性氧 (ROS) 形成水平的增加，当 ROS 产生被阻断时，PM 诱导的 EPC 和 BMSC 减少被有效阻止。 EPC 数量通过氧化应激介导的骨髓中 BMSC 数量的减少，以及 BMSC 生成 EPC 的减少”。有两个具体目标：1)：确定 PM 暴露对 BMSC 及其内皮分化的影响；2)：定义氧化应激在介导 PM 暴露对 BMSC 及其分化为 EPC 的影响中的作用 我们将证明 PM 暴露会导致骨中 BMSC 的数量和功能显着减少。我们将确定 BMSC 数量的减少是否是由于细胞凋亡增加或增殖减少所致。我们还将使用 eGFP 阳性 BMSC 进行骨髓移植 (BMT) 实验，以确定 PM 暴露是否会损害 BMSC 向细胞分化。在 PM 暴露环境中，EPC 可能会导致 EPC 数量和功能下降。为了确定 PM 暴露是否会对 BMSC 产生与慢性空气污染类似的影响，将使用暴露于空气污染的小鼠进行重复实验。我们将通过使用抗氧化剂 N-乙酰半胱氨酸或同时过度表达人铜/锌超氧化物歧化酶 (SOD) 抗氧化酶网络来阻止 ROS 产生，从而测试 PM 诱导的 ROS 产生是否会导致 BMSC 数量和功能下降。 1、细胞外 SOD3 和谷胱甘肽过氧化物酶减少 ROS 形成 我们还将使用带有 eGFP-BMSC 的 BMT 模型来确定 PM 诱导的氧化应激是否发挥作用。将进行实验以评估 ROS 在 BMSC 群体中的作用及其在暴露于空气污染长达 6 个月的小鼠中向 EPC 的分化。关于 PM 暴露和空气污染患者发生心血管疾病的机制的重要而新颖的信息，有助于探索预防和治疗与 PM 暴露相关的心血管疾病的新方法 1。