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

描述(申请人提供)：随着年龄的增长，组织中会发生一系列复杂的生物变化，这些变化往往会导致对损伤和疾病的再生反应能力受损。这会导致基本认知、感觉和运动功能的下降，进而降低生活质量。如果有鼓励组织再生的治疗方法，许多人类状况可能会得到显著改善。除了基于干细胞的策略外，替代方法还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，一些基因被诱导和抑制，特定的小调节RNA也协调差异表达。现在人们普遍认为，大多数基因是由小的非编码RNA调控的。在成体鳍组织中获得的初步数据显示，超过100个小RNA在再生过程中有差异表达，其中许多微小RNA(MiRNAs)被预测为调节已知的驱动再生过程的基因的表达。衰老对组织的再生能力有负面影响，据报道，在多种衰老模型中，miRNA的表达增加。由于我们的初步数据表明抑制关键的miRNAs是引起再生反应所必需的，我们假设特定的miRNA表达会随着年龄的增长而增加，并直接导致再生能力的降低。通过定义和比较全球小RNA和mRNA在老年人、成体和幼虫组织中的表达，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无法对组织损伤做出再生反应。在多种互补的再生范例中对miRNAs的充分表征将使识别促进或限制创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.