Epigenetic Modifications in Renal Fibrogenesis

描述（由申请人提供）：肾纤维化是慢性肾脏病的标志，是临床肾脏病学的突出问题。与急性肾损伤的生理性修复不同，进行性肾纤维化是一个独立的永久过程，即使最初的损伤已经消除，也无法停止。活化的成纤维细胞是纤维化的主要介质，并且从纤维化肾脏分离的成纤维细胞在体外培养时甚至不能恢复其静止状态。这种持续的成纤维细胞活化的分子机制尚不清楚。在全基因组甲基化筛选中，我们将Ras抑制剂RASAL 1鉴定为在来自纤维化肾脏的成纤维细胞中甲基化的13个基因之一，但在来自非纤维化肾脏的成纤维细胞中不甲基化。这项拨款申请的中心假设是“肾成纤维细胞中Ras原癌基因抑制因子RASAL 1的超甲基化阻止它们恢复到静止状态，并使纤维形成的进展永久化”。基于初步的数据，我们将阐明RASAL 1的高甲基化是否通过Ras过度活跃引起永久的成纤维细胞活化，最终导致肾纤维化。公共卫生相关性：肾纤维化是临床肾脏病学的主要问题，因为它导致肾功能的进行性丧失，需要透析或肾移植来避免即时死亡。具体的治疗，以停止-甚至逆转-尚未在临床上，使进一步了解相关的潜在病理机制。纤维化类似于伤口修复。然而，与伤口修复不同的是，一旦最初的损伤已经被遏制，纤维形成就不会停止，导致永久性疤痕组织形成，从而导致肾衰竭。纤维化过程在某些患者中未能停止的原因尚不清楚。本申请将阐明表观遗传变化的作用，这是相对稳定的DNA修饰，在肾纤维化。

DESCRIPTION (provided by applicant): Renal fibrosis is the hallmark of chronic kidney disease, a prominent problem in clinical nephrology. Unlike physiologic repair of acute kidney injury, progressive renal fibrosis is a self-contained perpetuated process, which fails to cease even when the initial insult has been eliminated. Activated fibroblasts are the main mediators of fibrosis, and fibroblasts isolated from fibrotic kidneys even fail to return to their quiescent state when cultured in vitro. The molecular mechanisms that underlie this persisting fibroblast activation are not yet known. In a genomewide methylation screen we identified the Ras inhibitor RASAL1 as one of 13 genes to be methylated in fibroblasts from fibrotic kidneys, but not in fibroblasts from non-fibrotic kidneys. The central hypothesis of this grant application is that 'hypermethylation of RASAL1, a suppressor of the Ras proto-oncogene, in renal fibroblasts prevents them from returning to their quiescent state and perpetuates progression of fibrogenesis". Based on the preliminary data we will elucidate if hypermethylation of RASAL1 causes perpetuated fibroblast activation via Ras hyperactivity, ultimately leading to renal fibrosis. PUBLIC HEALTH RELEVANCE: Renal fibrosis is a major problem in clinical Nephrology, because it causes progressive loss of kidney function, requiring dialysis or kidney transplantation to circumvent instant fatality. Specific therapies to halt - or even reverse - are not yet available in the clinic, making further understanding of the underlying pathomechanisms relevant. Fibrosis resembles wound repair. However, unlike wound repair, fibrogenesis does not cease once the initial insult has been contained, causing perpetuated scar tissue formation which results in kidney failure. The reason why the fibrotic process fails to stop in some patients is not known. This application will elucidate the role of epigenetic changes, which are relatively stable modifications of DNA, in renal fibrosis.