Juvenile microRNAs promoting healthier adult aging

摘要：本提案是对RFA的回应：青少年保护因素及其对衰老的影响（R 01） 鉴于它们广泛的调节作用，microRNA（miRNA）生物学知识对于研究它们的功能至关重要。 全面了解衰老。miRNA介导的调节模式的特殊之处在于， 单个miRNA可以靶向数百个基因，而多个miRNA可以靶向相同的基因。 该框架将miRNAs作为复杂表型的关键调节因子，通过整合多种 生物输入和输出。由miRNAs联合的多种途径和过程导致了 到高度复杂的网络图，以更好地了解衰老的生物学和应用， 治疗学发展。由于miRNA具有治疗用途，例如将外源性miRNA应用于 减轻有害的衰老相关基因的过度表达，我们的希望是操纵miRNA水平 将成为治疗衰老疾病的潜在工具。 我在发育生物学方面的工作启发了我去理解microRNA的作用， （miRNAs）在干细胞和癌症中的作用，以及在更复杂的生物体中， 衰老中的miRNAs我们鉴定了第一个参与衰老过程的miRNA（gerontomiR）lin-4。 在秀丽隐杆线虫中，lin-4的敲低降低了蠕虫的寿命，而过度表达lin-4则降低了蠕虫的寿命。 增加寿命。此外，miR-71和miR-246在C. elegans增加 中心blog 有趣的是，这些gerontomiR中的大多数在幼年/幼虫和早期成虫期间显示出峰值表达。 生命周期的各个阶段，但对成年人的正常衰老很重要。例如，lin-4和let-7播放 miR-71和miR-246在幼虫干细胞发育时间中起关键作用，而miR-71和miR-246是应激所必需的。 在幼虫中，所有这些反应都是下调的，并且是促进健康衰老所必需的。 此外，在个体动物的成年早期，miR-71和miR-246的表达水平增加， 与更长的个体寿命相关。在这项新的工作中，将确定额外的gerontomiR，并测试 假设这些老年miR在成人中的异时表达能够延长 寿命在C.优雅 最近，我们和其他人已经鉴定了各种在哺乳动物中上调或下调的miRNAs， 衰老，通过比较它们在年轻和老年小鼠中的肝脏或大脑特异性表达。我们还开始 鉴定可能是人类衰老的有用生物标志物的miRNA。考虑到miRNAs可能 调节人类衰老的过程，在这里，我们还将研究人类衰老的途径， Aim 1中鉴定的gerontomiRs的同源物可能在miRNAs调控细胞中起作用，并测试miRNAs是否调控细胞凋亡。 衰老的人类细胞和潜在的小鼠模型。

Summary: This proposal is responsive to RFA: Juvenile Protective Factors and Their Effects on Aging (R01) Given their broad regulatory roles, knowledge of microRNA (miRNA) biology is essential to a comprehensive understanding of aging. The mode of miRNA-mediated regulation is special in that hundreds of genes can be targeted by a single miRNA while multiple miRNAs can target the same gene. This framework commends miRNAs as key modulators of complex phenotypes by integrating multiple biological inputs and outputs. The multiplicity of pathways and processes that are united by miRNAs leads to highly complex network diagrams to better understand the biology of aging and for applications such as therapeutics development. Since miRNAs have therapeutic uses, e.g. application of exogenous miRNAs to alleviate over-expression of detrimental aging-associated genes, our hope is manipulation of miRNA levels would be a potential therapeutic tool in diseases of aging. My work in developmental biology inspired my move towards understanding the role of microRNAs (miRNAs) in stem cells and cancer in more complex organisms, and towards understanding roles for miRNAs in aging. We identified the first miRNA (gerontomiR) to be implicated in the aging process, lin-4. Knockdown of lin-4 in Caenorhabditis elegans decreased longevity of the worms, whereas over-expression of lin-4 increased longevity. Additionally, overexpression of miR-71 and miR-246 in C. elegans increased longevity. Interestingly, most of these gerontomiRs show peak expression during juvenile/larval and early adult phases of the lifecycle, and yet are important for normal aging in adults. For example, lin-4 and let-7 play key roles in stem cell developmental timing in larvae while miR-71 and miR-246 are required for stress response in larvae, yet all are down-regulated in the adult and are required to promote healthy aging. Additionally, increased expression levels of mir-71 and miR-246 in early adulthood of individual animals is associated with longer individual lifespan. In this new work will identify additional gerontomiRs and test the hypothesis that heterochronic expression of these gerontomiRs in the adult is capable of extending lifespan in C. elegans. Recently, we and other have identified various miRNAs that are up- or down-regulated during mammalian aging, by comparing their liver or brain-specific expression in younger and older mice. We have also begun to identify miRNAs that could be useful biomarkers of aging in humans. Given the possibility that miRNAs may regulate processes involved in human aging, here we will also examine the aging pathways that human homologues of the gerontomiRs identified in Aim 1 may function in and test if miRNAs regulate cell senescence of human cells and potentially, mouse models.