Role of miR193 in oxidized lipid induced pulmonary hypertension

miR193在氧化脂质诱导的肺动脉高压中的作用

基本信息

批准号：
9107288
负责人：
Mansoureh Eghbali
金额：
$ 57.19万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107288
关键词：
Acids Animal Model Atherosclerosis Biological Markers Blood Vessels Chronic lung disease Coculture Techniques Complex Data Deterioration Development Diagnostic Diet Disease Down-Regulation Early Diagnosis Endothelial Cells Enzymes Experimental Animal Model Experimental Designs Fatty Acids Heart failure Human Hydroxyeicosatetraenoic Acids Hypoxia IGF1R gene Inflammation Inflammatory Lipoxygenase Lung Lung Transplantation Measurement Mediating Medical MicroRNAs Modeling Mus Pathogenesis Pathway interactions Patients Plasma Play Production Publishing Pulmonary Hypertension Pulmonary artery structure RXR RXRA gene Rattus Regulation Role Severity of illness Smooth Muscle Myocytes Symptoms Testing Therapeutic Time Vascular remodeling Ventricular Wild Type Mouse arm base biomarker panel clinically relevant early detection biomarkers feeding improved macrophage monocyte mortality novel overexpression oxidized lipid pressure public health relevance pulmonary arterial hypertension receptor research study tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a non-curable chronic lung disease characterized by progressive increase in pulmonary arterial pressure leading to right ventricular (RV) heart failure. PAH is associated with inflammation and excessive proliferation of pulmonary artery smooth muscle cells and endothelial cells leading to severe pulmonary vascular remodeling. Interestingly, like in other inflammatory diseases such as atherosclerosis, it has been found that the levels of oxidized fatty acids such as hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) are upregulated in the lungs from patients with PAH as well as in hypoxic rats with pulmonary hypertension (PH). We recently discovered that the levels of HETEs and HODEs are also robustly elevated in the plasma of PAH patients and in rats with PH. We also discovered that miR193, a miRNA which targets lipoxygenase (LOX) enzymes involved in the production of oxidized fatty acids, is significantly downregulated in the lungs and plasma of PAH patients and in two experimental animal models of PH. Overexpression of miR193 in the lungs rescued pre-existing PH in rats and mice highlighting the therapeutic role of miR193 in reversing pulmonary vascular remodeling. To further examine the role of oxidized fatty acids in development of PH, we placed wild type mice on 15-HETE diet for 3 weeks and we found that 15- HETE containing is sufficient to trigger PH. We hypothesize that HETEs and HODEs may play a causal role in PH. Our preliminary results in the lungs of mice on 15-HETE diet also show: i) levels of miR193 were significantly reduced; ii) ED1-positive inflammatory macrophage/monocytes were increased; and iii) expression of interlukin-17 receptor D (IL17-RD), which is a target of miR193, is significantly increased. This proposal has three arms: i) Mechanistic arm to test the hypothesis that 15HETE diet alone is sufficient to induce PH in WT mice by regulating miR193 and its targets through transcription factor RXR-a; ii) Diagnostic arm to determine whether plasma oxidized fatty acids together with miR193 could serve as biomarker panel for PAH; and iii) Therapeutic arm to examine the role of miR193 for reversal of adverse vascular remodeling in PAH patients. Aim 1 will determine the role of RXRα/miR193/LOX pathway in development of PH induced by 15-HETE diet; Aim 2 will determine the role of miR193 targets IL-17RD and IGFR1 in development of PH induced by 15-HETE diet; and Aim 3 will examine the clinical relevance of oxidized fatty acids and miR193 in PAH patients. This proposal will provide for the first time pivotal information on the role of pro-inflammatory oxidized fatty acids and miR193 that modulate their levels in the regulation and development of pulmonary hypertension.

描述（由申请人提供）：肺动脉高压（PAH）是一种无法治愈的慢性肺部疾病，其特征是肺动脉压力进行性升高，导致右心室（RV）心力衰竭，与炎症和肺动脉过度增殖有关。平滑肌细胞和内皮细胞导致严重的肺血管象征性重塑，就像在动脉粥样硬化等其他炎症性疾病中一样，已发现脂肪等氧化酸的水平。羟基二十碳四烯酸 (HETE) 和羟基十八碳二烯酸 (HODE) 在 PAH 患者以及患有肺动脉高压 (PH) 的缺氧大鼠的肺部中表达上调，我们最近发现血浆中 HETE 和 HODE 的水平也大幅升高。我们还发现 miR193（一种针对脂氧合酶 (LOX) 的 miRNA）参与了 PAH 患者和 PH 大鼠的研究。氧化脂肪酸的产生在 PAH 患者的肺部和血浆中显着下调，并且在两种 PH 实验动物模型中，肺部过度表达 miR193 可以挽救大鼠和小鼠中先前存在的 PH，这凸显了 miR193 在逆转 PH 方面的治疗作用。为了进一步研究氧化脂肪酸在 PH 发展中的作用，我们让野生型小鼠接受 15-HETE 饮食 3 周，我们发现含有 15-HETE 足以引发 PH。我们认为 HETE 和 HODE 可能在 PH 中发挥因果作用。我们对 15-HETE 饮食的小鼠肺部的初步结果也表明：i) miR193 水平显着降低； ) ED1 阳性炎症巨噬细胞/单核细胞增加；以及 iii) 白细胞介素 17 受体 D (IL17-RD) 的表达，这是该提议分为三个部分：i) 机制部分，用于测试仅 15HETE 饮食就足以通过转录因子 RXR-a 调节 miR193 及其靶标来诱导 WT 小鼠的 PH 的假设；ii) 诊断部分；确定血浆氧化脂肪酸与 miR193 一起是否可以作为 PAH 的生物标志物组；以及 iii) 治疗组检查 miR193 的逆转作用；目标 1 将确定 RXRα/miR193/LOX 通路在 15-HETE 饮食诱导的 PH 发展中的作用；目标 2 将确定 miR193 靶标 IL-17RD 和 IGFR1 在 PH 发展中的作用。 15-HETE 饮食诱导；目标 3 将检查氧化脂肪酸和 miR193 在 PAH 患者中的临床相关性。该提案将首次提供关于促炎氧化脂肪酸和 miR193 作用的关键信息，调节其在肺动脉高压的调节和发展中的水平。