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: 9332457
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332457
• 关键词: Alpha Cell; Blood Vessels; Cardiac; Cell Differentiation process; Cell Survival; Cell Therapy; Cell Transplants; Cells; Communication; Endothelial Cells; Heart; 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; Stem cells; Testing; Therapeutic; Transplantation; Ubiquitination; Vascular Smooth Muscle; Work; angiogenesis; improved; mouse model; notch protein; novel; overexpression; preconditioning; repaired; response; 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.

项目摘要 心脏间充质干细胞（C-MSC）是一种独特的干细胞库，驻留在心脏 其在血管稳态和生理性血管细胞更新中起重要作用。 将C-MSC移植到心脏中已经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主要的技术挑战。我们报道了 低氧预处理（HP）可促进供者干细胞存活和HIF-1α- 依赖的方式。从机制上讲，C-MSC对HP的反应与HP水平相关。 激活Notch信号传导，干细胞中的细胞-细胞接触和通路，也介导 C-MSC的血管平滑肌细胞（VSMC）分化。此外，我们还发现了一个 Notch-regulated microRNA，miR-322，人类miR-424的啮齿类同源物， 据报道，通过阻断人HIF-1α亚型的降解来促进血管生成 内皮细胞在缺氧过程中，提出了一种新的机制之间的串扰Notch- 调节miR-322和HIF-1α。我们建议研究Notch-1和新的 确定的Notch-1靶点miR-322维持并加强HP对肿瘤细胞的有益作用。 血管细胞存活和干细胞的血管生成活性。我们还将确定 利用干细胞中的这些调节机制可以增强血管保护， 心肌梗死（MI）小鼠模型中的修复。有三个目标：目标1：测试 Notch信号转导调节HP在干细胞介导的肿瘤中的有益作用的假说 血管修复目的2：检验miR-322介导Notch 1之间串扰的假设 和HIF-1α信号传导来增强干细胞的活性。目的3：测试治疗效果 靶向Notch 1/miR-322轴增强干细胞介导的血管修复的潜力 和血管生成。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， 血管生成和增强C-MSC治疗的功效。