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，组织中发生了一系列复杂的生物学变化，这些变化通常导致对损伤和疾病进行再生反应的能力受损。这会导致基本的认知、感觉和运动功能下降，进而导致生活质量下降。如果能够获得促进组织再生的疗法，许多人类状况都可以得到显著改善。除了基于干细胞的策略外，其他方法利用非哺乳动物模型固有的再生能力来定义允许组织再生的分子事件。我们开发并验证了一个强大的斑马鱼再生模型，以揭示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也被协调差异表达。现在人们普遍认为大多数基因是由小的非编码rna调控的。在成年鱼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，其中许多microrna （mirna）被预测调节已知驱动再生过程的基因的表达。衰老会对组织的再生能力产生负面影响，据报道，在多种衰老模型中，miRNA表达增加。由于我们的初步数据表明，抑制关键miRNA对于引发再生反应是必要的，我们假设特定miRNA的表达会随着年龄的增长而增加，并直接导致再生能力的下降。通过定义和比较老龄、成体和幼虫组织中小RNA和mRNA的整体表达，以及体内miRNA-mRNA关系的机制评估，我们将阐明协调完成再生的分子和遗传途径。这些研究将使我们能够开始理解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。mirna在多种互补再生模式中的全面表征将使鉴定促进或限制损伤愈合和再生的关键调控事件成为可能。

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.