Notch1/miR-322 Axis in Stem Cell Mediated Vascular Repair

Notch1/miR-322 轴在干细胞介导的血管修复中的作用

• 批准号: 9923003
• 负责人: Muhammad Ashraf
• 金额: $ 62.14万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923003
• 关键词: Blood Vessels; Cardiac; Cell Differentiation process; Cell Survival; Cell Transplantation; Cells; Communication; Endothelial Cells; Heart; Heart Transplantation; Homeostasis; Homologous Gene; Human; Hypoxia; Impairment; Mediating; Mesenchymal Stem Cells; MicroRNAs; Molecular; Myocardial Infarction; Myocardial Ischemia; Notch Signaling Pathway; Pathway interactions; Physiological; Play; Protein Isoforms; Reporting; Rodent; Role; Signal Transduction; Smooth Muscle Myocytes; Testing; Therapeutic; Ubiquitination; Vascular Smooth Muscle; Work; angiogenesis; improved; mouse model; notch protein; novel; overexpression; preconditioning; repaired; response; stem cell therapy; stem cells; therapeutic evaluation

PROJECT SUMMARY Cardiac mesenchymal stem cells (C-MSC) are a unique pool of stem cells residing in the heart that play an important role in vascular homeostasis and physiological vascular cell turnover. Transplanting C-MSC into the heart has shown promise for vessel repair and angiogenesis, but poor survival of transplanted cells poses a major technical challenge. We reported that hypoxic preconditioning (HP) improves donor stem cell survival and angiogenesis in a HIF-1α- dependent manner. Mechanistically, C-MSC responses to HP correlate with the level of activation of Notch signaling, a cell-cell contact and pathway in stem cells that also mediates vascular smooth muscle cell (VSMC) differentiation of C-MSC. Moreover, we have identified a Notch-regulated microRNA, miR-322, the rodent homolog of human miR-424, which was reported to promote angiogenesis by blocking degradation of HIF-1α isoforms in human endothelial cells during hypoxia, suggesting a novel mechanism of crosstalk between Notch- regulated miR-322 and HIF-1α. We propose to investigate how Notch-1 and the newly identified Notch-1 target miR-322 sustain and potentiate the beneficial effects of HP on the vascular cell survival and angiogenic activity of stem cells. We will also determine whether harnessing these regulatory mechanisms in stem cells can enhance vessel protection and repair in a mouse model of myocardial infarction (MI). There are three aims: Aim 1: Test the hypothesis that Notch signaling regulates the beneficial effects of HP in stem cell-mediated vascular repair. Aim 2: Test the hypothesis that miR-322 mediates crosstalk between Notch1 and HIF-1α signaling in stem cells to enhance their activity. Aim 3: Test the therapeutic potential of targeting the Notch1/miR-322 axis to enhance stem cell-mediated vascular repair and angiogenesis in a mouse model of MI. Successful completion of the proposed studies will elucidate novel mechanisms associated with C-MSC mediated vascular repair and angiogenesis and enhance the efficacy of C-MSC therapy.

项目概要 心脏间充质干细胞 (C-MSC) 是心脏中独特的干细胞库 在血管稳态和生理血管细胞更新中发挥重要作用。 将 C-MSC 移植到心脏已显示出血管修复和血管生成的前景， 但移植细胞的存活率低是一个重大的技术挑战。我们报道称 低氧预处理 (HP) 可改善 HIF-1α- 中供体干细胞的存活和血管生成 依赖方式。从机制上讲，C-MSC 对 HP 的反应与 HP 的水平相关 Notch 信号传导的激活，干细胞中的一种细胞间接触和途径，也介导 C-MSC 的血管平滑肌细胞 (VSMC) 分化。此外，我们还确定了一个 Notch 调节的 microRNA，miR-322，人类 miR-424 的啮齿动物同源物， 据报道，通过阻止人体内 HIF-1α 亚型的降解来促进血管生成 缺氧期间内皮细胞的变化，表明Notch-之间存在一种新的串扰机制 调节 miR-322 和 HIF-1α。我们建议研究 Notch-1 和新的 确定的 Notch-1 靶标 miR-322 维持并增强 HP 对 血管细胞存活和干细胞的血管生成活性。我们还将确定是否 利用干细胞中的这些调节机制可以增强血管保护和 心肌梗死（MI）小鼠模型中的修复。共有三个目标： 目标 1：测试 Notch 信号传导调节 HP 在干细胞介导中的有益作用的假设 血管修复。目标 2：检验 miR-322 介导 Notch1 之间串扰的假设 干细胞中的 HIF-1α 信号传导可增强其活性。目标 3：测试治疗效果 靶向Notch1/miR-322轴增强干细胞介导的血管修复的潜力 以及 MI 小鼠模型中的血管生成。成功完成拟议的研究将 阐明与 C-MSC 介导的血管修复相关的新机制 血管生成并增强 C-MSC 治疗的功效。