Targeting oxidative stress-induced epigenetic reprogramming in fibrotic disease

母公司资助R15项目摘要(1R15DK121362-01A1) 这项拟议研究的目标是评估氧化应激是否会导致表观遗传学改变。 是肾脏纤维化的驱动因素。肾脏多发性或反复急性损伤，原因是 长期接触毒物会导致肾脏纤维化，这是一种对 目前还没有治疗方法。环境毒物是慢性肾脏的主要危险因素 疾病。氧化应激的产生是环境毒物最常见的特性。 除外源性氧化应激外，内源性因素或基础 肾脏患者的特点，如高龄、糖尿病和肾性高血压也可 使个体更容易受到氧化应激水平的影响 人口。除了遗传变化外，表观遗传机制在 基因转录调控。然而，表观遗传变化的协调序列 在慢性肾脏病过程中，驱动氧化应激导致的肾脏纤维化仍不清楚。我们的初步数据 研究表明，持续暴露在氧化应激下可以诱导PEMT和诱导多能干细胞- 如(IPSCs)功能，已知与纤维化有关。根据初步数据，我们 “促氧化肾毒剂诱导的表观遗传重编程是驱动因素”假说 部分EMT对肾小管上皮细胞重塑的影响 纤维形成“。为了实现这一建议的目标，我们将首先确定时间序列和 氧化应激诱导的肾小管纤维化过程中表观遗传学改变的全球分布 上皮细胞采用体外细胞培养和体内动物模型。第二，表观遗传学的作用 肾上皮细胞获得IPSCs和PEMT特性的靶基因重编程 以及它们对成纤维细胞活化为产生细胞外基质的肌成纤维细胞的影响将被确定。 最后，为了评估表观遗传疗法在抑制肾脏纤维化方面的临床意义，我们将 评价逆转纤维化肾细胞表观遗传学改变能否恢复正常肾脏 利用体外和体内模型研究上皮细胞的特性和功能。肾脏纤维化是一个很好的- 确立了慢性肾脏病发展的病理阶段。这项研究将导致更好的 氧化应激诱导纤维化的表观遗传学分子机制的认识 在CKD期间。识别肾脏纤维化的靶分子将有助于建立药理学 干预措施可以防止急性组织损伤进展到不可逆转的阶段 肾脏和其他靶器官可能出现纤维化。

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.