MicroRNA regulation of angiogenesis in aging

项目摘要 血管修复/血管生成受损是老年患者的主要临床问题，常导致缺血性 外周动脉和心血管疾病。最近的研究集中在改善老龄化的策略上。 细胞的血管生成能力和随后的组织修复。MicroRNAs(MiRNAs)已成为关键 血管功能的调节器。我们认为在衰老过程中后肢miRNAs的表达发生了变化 导致血管功能随年龄增长而下降。在众多的miRNA中，miR-34a具有 有望成为器官老化的生物标记物。它与骨髓源性功能受损有关 心血管疾病患者的单个核细胞。值得注意的是，miRNAs的潜在机制 血管生成的调控，特别是在衰老过程中的调控，目前还不完全清楚。我们的中心假设是 MiR-34a通过直接抑制GCH1/BH4通路而延缓衰老过程中的血管生成 氧化应激加速衰老，激活炎症体，抑制有丝分裂。 值得注意的是，关于miRNAs调控血管生成的信息很少，特别是在衰老的情况下。这 假设是在仔细分析了该领域已发表的工作并产生了一些 我们实验室的关键初步数据。我们计划测试我们的中心假设并通过以下方式实现我们的目标 追求三个具体目标。在目标1中，我们将确定miR-34a在调节 衰老中的血管生成。我们的工作假设是miR-34a通过损伤抑制衰老中的血管生成 内皮祖细胞(EPC)功能。在目标2中，我们将描述GCH1/BH4通路的作用 关于miR-34a在衰老过程中引起EPC功能障碍的研究。我们假设miR-34a延缓了EPC在 通过直接抑制GCH1/BH4途径而衰老，这会导致过度的氧化应激，从而减少 端粒酶活性通过抑制沉默信息调节因子1(SIRT1)而加速衰老。在……里面 目的3，我们将确定miR-34a在后肢老化过程中如何影响有丝分裂和炎性小体的激活。 缺血症。GCH1/BH4缺乏导致活性氧(ROS)水平升高，这可能 激活炎症小体，从而抑制有丝分裂，加速衰老过程。我们假设 MIR-34a通过Nlrp3抑制衰老中的有丝分裂吞噬(NOD样受体家族，含3的吡咯域) 炎性小体激活，可由线粒体超氧化物的积累触发。少校 这项研究的意义在于它将确定miRNAs在衰老过程中如何调节血管生成功能。 一旦获得了这样的知识，就有可能开发出新的治疗抢救方法。 如今，越来越多的老年患者血管生成受损。

Project Summary Impaired vascular repair/angiogenesis is a major clinical problem in aged patients that often leads to ischemic peripheral artery and cardiovascular diseases. Recent studies have focused on strategies to improve aged cells’ angiogenesis capability and subsequent tissue repair. MicroRNAs (miRNAs) have emerged as crucial regulators of vascular function. We propose that altered expression of miRNAs in hind limbs during aging contributes to the age-dependent decline in vascular function. Among the numerous miRNAs, miR-34a has shown promise as a biomarker for organ aging. It correlates with impaired function of bone marrow-derived mononuclear cells from patients with cardiovascular disease. Remarkably, the mechanism underlying miRNAs’ regulation of angiogenesis, especially in aging, is not completely understood. Our central hypothesis is that the miR-34a retards angiogenesis in aging by directly inhibiting the GCH1/BH4 pathway resulting in excessive oxidative stress, which accelerates senescence, activates inflammasome, and suppresses mitophagy. Remarkably, little information exists on miRNAs regulation of angiogenesis, especially under aging. This hypothesis was formulated after a careful analysis of published work in the field and the generation of some key preliminary data in our laboratory. We plan to test our central hypothesis and accomplish our objective by pursuing three specific aims. In Aim 1, we will establish the critical role of miR-34a in regulation of angiogenesis in aging. Our working hypothesis is that miR-34a inhibits angiogenesis in aging via impairing endothelial progenitor cell (EPC) functions. In Aim 2, we will delineate the effect of the GCH 1/BH4 pathway on miR-34a induced EPC dysfunction in aging. We hypothesize that that miR-34a retards EPC functions in aging by directly inhibiting the GCH1/BH4 pathway, which results in excessive oxidative stress that decreases telomerase activity and accelerates senescence via suppressing Silent Information Regulator 1 (SIRT1). In Aim 3, we will determine how miR-34a affects mitophagy and inflammasome activation in aging after hind limb ischemia. Deficiency of GCH1/BH4 results in elevated reactive oxygen species (ROS) level, which may activate inflammasome, and thus inhibit mitophagy and accelerate the aging process. We hypothesize that miR-34a inhibits mitophagy in aging via Nlrp3 (NOD-like receptor family, pyrin domain containing 3) inflammasome activation, which can be triggered by accumulation of mitochondrial superoxide. The major significance of this study is that it will determine how miRNAs regulate angiogenic functions during aging. Once such knowledge is gained, it is possible that new modalities may be developed to therapeutically rescue impaired angiogenesis in the growing number of aging patients today.