Investigating the permissive role of small RNAs on aging and tissue regeneration

描述（由申请人提供）：随着年龄的增长，组织中会发生许多复杂的生物学变化，这些变化通常会导致对损伤和疾病的再生反应能力受损。这导致基本认知、感觉和运动功能下降，进而降低生活质量。如果有促进组织再生的疗法，许多人类疾病都可以得到显著改善。除了基于干细胞的策略之外，替代方法利用非哺乳动物模型的固有再生能力来定义允许组织再生的分子事件。我们已经开发并验证了一个强大的斑马鱼再生模型，以解开脊椎动物组织再生的复杂过程。我们的研究表明，在再生过程中，许多基因被诱导和抑制，特定的小调控RNA也协同差异表达。现在广泛接受的是，大多数基因由小的非编码RNA调控。在成体鳍组织中获得的初步数据显示，超过100种小RNA在再生过程中差异表达，并且预测这些microRNA（miRNAs）中的许多调节已知驱动再生过程的基因的表达。衰老对组织的再生能力产生负面影响，据报道，miRNA表达在多种衰老模型中增加。由于我们的初步数据表明，抑制关键的miRNA是必要的，以引发再生反应，我们假设特定的miRNA表达将随着年龄的增长而增加，并直接导致再生能力下降。通过定义和比较全球小RNA和mRNA在老年人，成年人和幼虫组织中的表达，再加上体内miRNA-mRNA关系的机制评估，我们将阐明协调功能以实现再生的分子和遗传途径。这些研究将使我们能够开始了解miRNA在衰老和再生中的作用，更广泛地说，有助于解释为什么哺乳动物不能对组织损伤做出再生反应。在多个互补再生范例中对miRNAs的充分表征将使得鉴定促进或限制创伤愈合和再生的关键调控事件成为可能。 公共卫生相关性：与年龄相关的疾病和损伤导致的组织损失是生活质量下降的主要原因。了解组织再生背后的复杂信号通路将为开发新的治疗方法提供新的途径，以帮助减缓和/或预防与年龄相关的组织损失。

DESCRIPTION (provided by applicant): With age, a host of complex biological changes occur in tissues which often result in an impaired capacity to mount a regenerative response to injury and disease. This leads to decreases in basic cognitive, sensory and motor functions and, in turn, a decreased quality of life. Numerous human conditions could be significantly improved if therapies that encourage tissue regeneration were available. In addition to stem cell-based strategies, alternative approaches exploit the inherent regenerative capacity of non-mammalian models to define the molecular events that permit tissue regeneration. We have developed and validated a powerful zebrafish regeneration model to unravel the complex process of vertebrate tissue regeneration. Our studies indicate that a number of genes are induced and repressed over the course of the regenerative process and that specific small regulatory RNAs are also coordinately differentially expressed. It is now widely accepted that the majority of genes are regulated by small non-coding RNAs. Preliminary data obtained in adult fin tissue revealed that over 100 small RNAs are differentially expressed during regeneration and many of these microRNAs (miRNAs) are predicted to regulate the expression of genes known to drive the regenerative process. Aging negatively impacts tissues' regenerative capacity and miRNA expression is reportedly increased in multiple models of aging. Since our preliminary data suggests that repression of key miRNAs is necessary to elicit a regenerative response, we hypothesize that specific miRNA expression will increase with age and directly leads to decreased regenerative capacity. By defining and comparing global small RNA and mRNA expression in aged, adult, and larval tissue coupled with mechanistic evaluation of miRNA-mRNA relationships in vivo, we will shed light on the molecular and genetic pathways that coordinately function to accomplish regeneration. These studies will put us in a position to begin to understand the role of miRNA in aging and regeneration and more broadly, help to explain why mammals fail to respond to tissue injury with a regenerative response. The full characterization of miRNAs in multiple complementary regeneration paradigms will make possible the identification of the key regulatory events that promote or limit wounding healing and regeneration. PUBLIC HEALTH RELEVANCE: Tissue loss from age-related disease and injury is a major cause of decreased quality of life. Understanding the complex signaling pathways that underly tissue regeneration will provide new avenues for developing novel therapeutics to help slow and/or prevent age-related tissue loss.