Targeting oxidative stress-induced epigenetic reprogramming in fibrotic disease

这项研究的目的是评估氧化应激诱导的表观遗传变化是否 作为肾脏纤维化的驱动因素。多个或反复急性损伤的肾脏，由于 慢性接触毒物导致肾纤维化的发展，这是一种不可逆的疾病， 目前还没有治疗方法。环境毒物是慢性肾脏病的主要危险因素 疾病氧化应激的产生是环境毒物最常见的特性。 除外源性氧化应激外，内源性因素或基本 肾病患者的特征如高龄、糖尿病和肾性高血压也可 与一般人相比， 人口除了遗传变化外，表观遗传机制在以下方面发挥重要作用： 基因的转录调控。然而，表观遗传改变的协调序列， 在CKD期间驱动氧化应激诱导的肾纤维化仍然未知。我们的初步数据 揭示了持续暴露于氧化应激诱导pEMT和诱导多能干细胞- 类似（iPSCs）的特征，已知与纤维化相关。根据初步数据，我们 假设“由促氧化剂肾毒性物质诱导的表观遗传重编程作为驱动因素 通过部分EMT和干性导致肾小管上皮细胞的细胞重塑， 纤维化”。为了实现这个建议的目标，我们将首先确定时间顺序， 氧化应激诱导的肾小管纤维化过程中表观遗传学改变的总体分布 使用体外细胞培养和体内动物模型的上皮细胞。第二，表观遗传的作用 iPSC靶基因重编程和肾上皮细胞获得的pEMT特征 并确定它们对成纤维细胞活化为ECM产生肌成纤维细胞的影响。 最后，为了评价表观遗传学治疗在抑制肾纤维化中的临床意义，我们将 评估逆转纤维化肾细胞中的表观遗传改变是否恢复正常肾 使用体外和体内模型研究上皮特征和功能。肾纤维化是一种- 在CKD的发展中建立病理阶段。这项研究将导致更好的 对氧化应激诱导纤维化的基于表观遗传学的分子机制的理解 CKD期间。肾纤维化靶分子的鉴定将有助于建立肾纤维化的药理学机制 干预措施，可以防止从急性组织损伤进展到不可逆的阶段， 肾纤维化和潜在的其他靶器官。

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.