The role of microRNA-210 in regulating oxidative stress in patients with peripheral artery disease

microRNA-210在调节外周动脉疾病患者氧化应激中的作用

基本信息

批准号：
10817332
负责人：
Panagiotis Koutakis
金额：
$ 14.51万
依托单位：
BAYLOR UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10817332
关键词：
3&apos Untranslated Regions Acute Affect Age Age Years Aging American Amputation Aortic Diseases Apoptosis Binding Biological Markers Bypass Cell Respiration Coronary Data Diagnosis Disease Disease Progression Evaluation Functional disorder Gastrocnemius Muscle Gene Expression General Population Generations Genetic Transcription Glycolysis Goals HIF1A gene Hindlimb Histologic Homologous Gene Hyperoxia Hypoxia Impairment In Vitro Individual Inflammation Inhibition of Apoptosis Intervention Iron Ischemia Laboratories Length of Stay Life Style Lipid Peroxidation Lower Extremity Malondialdehyde Messenger RNA MicroRNAs Mitochondria Modeling Morbidity - disease rate Muscle function Myopathy Necrosis Nucleotides Oxidation-Reduction Oxidative Stress Oxygen Patients Peripheral arterial disease Physical Function Procedures Prognosis Proteins Protocols documentation Quality of life Regulator Genes Reperfusion Injury Reperfusion Therapy Repression Respiration Role Sampling Serum Skeletal Muscle Sulfur Testing Therapeutic Tissues Transcript Translations United States Untranslated RNA Vascular blood supply Vascularization Walking Work angiogenesis artery occlusion carbonyl group cardiovascular risk factor circulating microRNA comparison control cytochrome c oxidase hypoxia inducible factor 1 improved individualized medicine inhibitor mRNA Expression mimetics mitochondrial dysfunction mitochondrial metabolism mortality normoxia novel operation posttranscriptional potential biomarker reduced muscle mass respiratory response revascularization surgery scaffold therapeutic target

项目摘要

Abstract Peripheral artery disease (PAD) affects 8.5 million of Americans over 40 years of age. Recent evidence from out work and others suggest the central role of oxidative stress in the pathophysiology of PAD and its association with greater walking impairment and decline in quality of life. Few therapeutic treatments can improve walking distances and quality of life in PAD patients. A new emerging therapeutic approach for PAD is the usage of mircroRNAs (miRs). miRs are endogenous 21∼25 nucleotides noncoding RNA, that can regulate posttranscriptional gene expression. The most common mechanism of action of miRs is by binding to the 3' un- translated region of a target mRNA and thereby reducing mRNA expression or protein translation. Circulating miRNAs, represent potential biomarkers for the diagnosis and prognosis of PAD and a starting point for individualized treatment. Recent evidence in PAD and hindlimb ischemia models have identified miR-210 as a master regulator of gene expression under hypoxic conditions. Preliminary work from our laboratory has demonstrated that miR-210 in the serum and gastrocnemius samples is increased and positively correlated with disease progression. Furthermore, we have identified that revascularization operations can decrease circulating miR-210 in the serum of PAD patients six-months after the operation. It has been shown that miR-210 can negatively regulate mitochondrial respiratory activity and increase reactive species generation by inhibiting the ISCU (iron-sulfur cluster scaffold homolog) and COX10 (cytochrome c oxidase assembly protein). Thus, our central hypothesis, is that miR-210 gene expression is a master regulator of oxidative stress and is associated with mitochondrial dysfunction, oxidative metabolism, walking function and quality of life. Aim #1: miR-210 gene expression in the gastrocnemius and serum of patients with PAD, is different than healthy age matched controls, and correlates with oxidative stress, oxidative metabolism, mitochondrial function, walking function and quality of life. Aim #2: Endovascular and open bypass revascularization procedures can regulate oxidative stress by decreasing miR-210 expression in the gastrocnemius and serum of PAD patients and improve mitochondrial function, oxidative metabolism, walking function and quality of life. Aim #3: Utilize in-vitro studies in a novel normoxia/hypoxia/hyperoxia model of PAD to determine the extent to which gene expression changes by inducing/inhibiting miR-210 gene expression and its interactions with mRNA expression.

抽象的外周动脉疾病 (PAD) 影响着 850 万 40 岁以上的美国人。工作和其他人表明氧化应激在 PAD 病理生理学及其关联中的核心作用步行障碍更大，生活质量下降，很少有治疗可以改善步行。 PAD 患者的距离和生活质量是一种新兴的 PAD 治疗方法。微小RNA（miR）是内源性21-25个核苷酸的非编码RNA，可以调节。 miR最常见的作用机制是通过与3'un-结合。靶 mRNA 的翻译区域，从而减少 mRNA 表达或蛋白质翻译。 miRNA 代表了 PAD 诊断和预后的潜在生物标志物，也是 PAD 诊断和预后的起点 PAD 和后肢缺血模型的最新证据已确定 miR-210 是一种个体化治疗。我们实验室的初步工作已经完成了缺氧条件下基因表达的主要调控。证明血清和腓肠肌样本中的 miR-210 增加并与此外，我们发现血运重建手术可以减少循环。术后六个月 PAD 患者血清中的 miR-210 研究表明，miR-210 可以发挥作用。通过抑制线粒体呼吸活性来负调节线粒体呼吸活动并增加活性物质的产生 ISCU（铁硫簇支架同源物）和 COX10（细胞色素 c 氧化酶组装蛋白）。中心假设是，miR-210 基因表达是氧化应激的主要调节因子，并且与与线粒体功能障碍、氧化代谢、行走功能和生活质量有关。目标#1：PAD 患者腓肠肌和血清中的 miR-210 基因表达与健康人不同年龄匹配的对照，并与氧化应激、氧化代谢、线粒体功能、步行相关功能和生活质量。目标#2：血管内和开放式旁路血运重建手术可以通过以下方式调节氧化应激：降低 PAD 患者腓肠肌和血清中 miR-210 的表达并改善线粒体功能、氧化代谢、行走功能和生活质量。目标#3：利用新型 PAD 正常氧/缺氧/高氧模型的体外研究来确定 PAD 的程度通过诱导/抑制 miR-210 基因表达及其与 mRNA 的相互作用来改变基因表达表达。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of Age and Acute-Moderate Intensity Exercise on Biomarkers of Renal Health and Filtration.

DOI：
10.3390/biology11040527
发表时间：
2022-03-30
期刊：
Biology
影响因子：
4.2
作者：
通讯作者：

Shared and distinct mechanisms of skeletal muscle atrophy: A narrative review.

DOI：
10.1016/j.arr.2021.101463
发表时间：
2021-11
期刊：
Ageing research reviews
影响因子：
13.1
作者：
Wilburn D;Ismaeel A;Machek S;Fletcher E;Koutakis P
通讯作者：
Koutakis P

Skeletal muscle MiR-210 expression is associated with mitochondrial function in peripheral artery disease patients.

DOI：
10.1016/j.trsl.2022.03.003
发表时间：
2022-08
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
0
作者：
Ismaeel A;Fletcher E;Miserlis D;Wechsler M;Papoutsi E;Haynatzki G;Smith RS;Bohannon WT;Koutakis P
通讯作者：
Koutakis P

Phytochemicals as Therapeutic Interventions in Peripheral Artery Disease.

DOI：
10.3390/nu13072143
发表时间：
2021-06-22
期刊：
Nutrients
影响因子：
5.9
作者：
Ismaeel A;Greathouse KL;Newton N;Miserlis D;Papoutsi E;Smith RS;Eidson JL;Dawson DL;Milner CW;Widmer RJ;Bohannon WT;Koutakis P
通讯作者：
Koutakis P

Endothelial cell-derived pro-fibrotic factors increase TGF-β1 expression by smooth muscle cells in response to cycles of hypoxia-hyperoxia.

DOI：
10.1016/j.bbadis.2021.166278
发表时间：
2022-01-01
期刊：
Biochimica et biophysica acta. Molecular basis of disease
影响因子：
0
作者：
Ismaeel A;Miserlis D;Papoutsi E;Haynatzki G;Bohannon WT;Smith RS;Eidson JL;Casale GP;Pipinos II;Koutakis P
通讯作者：
Koutakis P