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Targeting oxidative stress-induced epigenetic reprogramming in fibrotic disease

针对纤维化疾病中氧化应激诱导的表观遗传重编程

基本信息

批准号：
10606293
负责人：
Kamaleshwar P Singh
金额：
$ 36.45万
依托单位：
TEXAS TECH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606293
关键词：
Aberrant DNA Methylation Acute Animal Model Antioxidants Arsenic Automobile Driving Biological Assay Cell Culture Techniques Cells Cellular Morphology ChIP-seq Characteristics Chronic Chronic Kidney Failure Coculture Techniques DNA DNA Methylation Data Development Diabetes Mellitus Disease Early Diagnosis Elderly Endogenous Factors Epigenetic Process Epithelial Epithelial Cells Event Exposure to Extracellular Matrix Fibroblasts Fibrosis Folic Acid Funding Gene Expression Gene Expression Regulation General Population Generations Genes Goals Grant Histones Hydrogen Peroxide In Vitro Individual Inflammation Injury Injury to Kidney Intervention Kidney Laboratories Link Molecular Mutation Myofibroblast Organ Outcome Study Oxidative Stress Paracrine Communication Parents Pathologic Patients Pharmacology Play Pluripotent Stem Cells Prevention Process Property Reactive Oxygen Species Renal Hypertension Renal function Reporting Risk Factors Role Signal Transduction Source System Testing Therapeutic Tissues Toxic Environmental Substances Toxicant lead Transcriptional Regulation Tubular formation base clinically significant early detection biomarkers effective therapy epigenetic therapy fibrogenesis histone modification in vitro Model in vivo in vivo Model induced pluripotent stem cell interstitial kidney cell kidney epithelial cell kidney fibrosis mouse model nephrogenesis nephrotoxicity paracrine prevent promoter public health relevance restoration stem cell genes stem cells stem-like cell stemness toxicant wound healing

项目摘要

Project Summary of Parent funded R15 (1R15DK121362-01A1) The goal of this proposed study is to evaluate whether oxidative stress-induced epigenetic changes act as a driving factor for fibrosis in kidney. Multiple or repeated acute injuries to the kidney due to chronic exposure to toxicants lead to the development of kidney fibrosis, an irreversible disease for which there is no current treatment. Environmental toxicants are major risk factors for chronic kidney diseases. The generation of oxidative stress is the most common property of environmental toxicants. In addition to the exogenous sources of oxidative stress, the endogenous factors or basic characteristics of renal patients such as advanced age, diabetes and renal hypertension can also predispose the individuals to increasing levels of oxidative stress compared with the general population. In addition to genetic changes, the epigenetic mechanisms play an important role in transcriptional regulation of genes. However, the coordinated sequences of epigenetic alterations that drive oxidative stress-induced kidney fibrosis during CKD remain unknown. Our preliminary data revealed that persistent exposure to oxidative stress induces pEMT and induced pluripotent stem cell- like (iPSCs) feature, that are known to be associated with fibrosis. Based on preliminary data we hypothesize that “epigenetic reprogramming induced by pro-oxidant nephrotoxicants acts as a driver of cellular remodeling of kidney tubular epithelial cells through partial EMT and stemness leading to fibrogenesis”. To achieve the goal of this proposal, we will first Identify the temporal sequence and global distribution of epigenetic alterations during oxidative stress-induced fibrosis in kidney tubular epithelial cells using in vitro cell culture and in vivo animal models. Secondly, the role of epigenetic reprogramming of target genes for iPSCs and pEMT characteristics acquired by kidney epithelial cells and their impact on activation of fibroblast into ECM-producing myofibroblast will be determined. Finally, to evaluate the clinical significance of epigenetic therapy in inhibition of kidney fibrosis, we will evaluate whether reversal of epigenetic alterations in fibrotic kidney cells restores normal kidney epithelial characteristics and functions using in vitro and in vivo models. Kidney fibrosis is a well- established pathological stage in the development of CKD. This study will lead to a better understanding of the epigenetics-based molecular mechanism for oxidative stress-induced fibrosis during CKD. Identification of target molecules in kidney fibrosis will help to establish pharmacological interventions that could prevent the progression from acute tissue damage to an irreversible stage of fibrosis in the kidney and potentially in other target organs.

家长资助的 R15 (1R15DK121362-01A1) 项目摘要这项研究的目的是评估氧化应激是否诱导表观遗传变化作为肾脏纤维化的驱动因素。由于以下原因导致肾脏多次或反复急性损伤长期接触有毒物质会导致肾纤维化，这是一种不可逆转的疾病目前尚无治疗方法。环境毒物是慢性肾病的主要危险因素疾病。氧化应激的产生是环境毒物最常见的特性。除了外源性氧化应激外，内源性因素或基本因素肾脏病患者的特征，如高龄、糖尿病和肾性高血压也可以与一般人相比，个体更容易遭受氧化应激水平的增加人口。除了遗传变化外，表观遗传机制也发挥着重要作用。基因的转录调控。然而，表观遗传改变的协调序列 CKD 期间氧化应激诱导的肾纤维化的驱动因素仍不清楚。我们的初步数据研究表明，持续暴露于氧化应激会诱导 pEMT 并诱导多能干细胞 - 像（iPSC）特征，已知与纤维化相关。根据初步数据我们假设“促氧化肾毒物诱导的表观遗传重编程充当驱动因素通过部分 EMT 和干性对肾小管上皮细胞进行细胞重塑纤维发生”。为了实现该提案的目标，我们将首先确定时间序列并氧化应激诱导肾小管纤维化过程中表观遗传改变的整体分布使用体外细胞培养和体内动物模型来研究上皮细胞。其次，表观遗传的作用肾上皮细胞获得的 iPSC 和 pEMT 特征的靶基因重编程并将确定它们对成纤维细胞活化为产生 ECM 的肌成纤维细胞的影响。最后，为了评估表观遗传学治疗抑制肾纤维化的临床意义，我们将评估逆转纤维化肾细胞的表观遗传改变是否可以恢复正常的肾脏使用体外和体内模型研究上皮特征和功能。肾脏纤维化是一种 CKD 发展的病理阶段已确定。这项研究将带来更好的结果了解基于表观遗传学的氧化应激诱导纤维化的分子机制慢性肾病期间。肾纤维化靶分子的鉴定将有助于建立药理学可以防止急性组织损伤发展到不可逆转阶段的干预措施肾脏纤维化以及其他目标器官的潜在纤维化。