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）是居住在心脏中的独特的干细胞池 该在血管稳态和物理血管细胞更新中起着重要作用。 将C-MSC移植到心脏上已显示出对血管修复和血管生成的希望， 但是，移植细胞的存活不良构成了重大的技术挑战。我们报告了这一点 缺氧预处理（HP）改善了HIF-1α-的供体干细胞存活和血管生成 依赖方式。从机械上讲，C-MSC对HP的反应与 Notch信号传导的激活，干细胞中的细胞电池接触和途径也介导 C-MSC的血管平滑肌细胞（VSMC）分化。而且，我们已经确定了 Notch调节的MicroRNA，miR-322，人类mir-424的啮齿动物同源物，是 据报道，通过阻断人类HIF-1α同工型的降解来促进血管生成 缺氧期间的内皮细胞，表明Notch-之间的串扰机理 调控miR-322和HIF-1α。我们建议调查Notch-1和新的 确定Notch-1目标miR-322维持并潜在惠普对 干细胞的血管细胞存活和血管生成活性。我们还将确定是否 在干细胞中利用这些调节机制可以增强血管保护和 在心肌梗塞（MI）的小鼠模型中修复。有三个目标：目标1：测试 Notch信号传导调节HP对干细胞介导的有益作用的假设 血管修复。目标2：测试miR-322介导Notch1之间的串扰的假设 干细胞中的HIF-1α信号传导以增强其活性。目标3：测试治疗性 靶向Notch1/miR-322轴以增强干细胞介导的血管修复的潜力 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型机制和 血管生成并提高C-MSC治疗的效率。