Targeted Delivery of iPS-Endothelial Cells for the Repair of Cardiovascular Injur

iPS 内皮细胞的靶向递送用于修复心血管损伤

基本信息

  • 批准号:
    8574003
  • 负责人:
  • 金额:
    $ 34.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cell-based therapies for cardiovascular diseases (CVD) have proliferated over the past decade, but with limited success. The major hurdles for successful cell therapies are 1) cell type selection (e.g. progenitor vs. differentiated), 2) time or cell delivery (e.g. acute vs. chronic), 3) cell delivery mode (e.g. peripheral vs. directly into tissue), 4) rejection of transplanted cells (e.g. autologous vs. heterologous), and most importantly, 5) targeting delivery of cells to damaged organs to maximize therapeutic effects. We have developed an innovative strategy to overcome these hurdles by i.v. transfusing endothelial cells (ECs) overexpressing neutrophil interleukin-8 (IL8) receptors into rats with endoluminal injury of the carotid artery or myocardial infarction. Studies outlined in this proposa will extend this targeted cell delivery strategy to a more applicable stem cell type, autologous iPS-ECs (induced pluripotent endothelial stem cells); to avoid possible cell rejection problems in future translational and/or clinical studies and enhances the efficacy of tissue repair. We will delineate the mechanism(s) of the protective effects of i.v. administered adult ECs or iPS-ECs overexpressing IL8RA and IL8RB in rats with experimental vascular or cardiac injury. We hypothesize that adult ECs or iPS-ECs that overexpress IL8 receptors will mimic the behavior of neutrophils that target and adhere to injured tissues (e.g. to endoluminal surface and adventitia of injured arteries) and in doing so will compete with and inhibit neutrophil infiltration and attenuate subsequent inflammatory responses and structural and functional damage to tissues. The Aims of this proposal are: 1) Generation of induced pluripotent endothelial stem cells (iPS-ECs) that overexpress neutrophil interleukin-8 (IL8) receptor genes (IL8RA and IL8RB) for targeted cell delivery to injured vascular and cardiac tissues.2) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8 receptors (IL8RA and/or IL8RB) promotes structural and functional recovery of arteries following endoluminal vascular injury. 3) To test the hypothesis that targeted delivery of iPS-ECs or adult ECs overexpressing neutrophil IL8RA and IL8RB promotes structural and functional recovery of the left ventricle (LV) following experimentally induced myocardial infarction (MI). The results of the proposed studies are significant because they are expected to provide an innovative strategy for therapeutic interventions for cardiovascular injury. In addition, it is expected that the results wll fundamentally advance the field of cell-based therapy by providing a noninvasive and cost effective treatment modality.
描述(由申请人提供):心血管疾病(CVD)的细胞疗法在过去十年中激增,但取得的成功有限。成功细胞疗法的主要障碍是 1) 细胞类型选择(例如祖细胞与分化细胞)、2) 时间或细胞递送(例如急性与慢性)、3) 细胞递送模式(例如外周细胞与直接进入组织)、4) 移植细胞的排斥(例如自体与异源),最重要的是 5) 将细胞靶向递送至受损器官以最大化 治疗效果。我们制定了一项创新策略,通过静脉注射克服这些障碍。将过度表达中性粒细胞白细胞介素 8 (IL8) 受体的内皮细胞 (EC) 输注至颈动脉腔内损伤或心肌梗塞的大鼠体内。本提案中概述的研究将把这种靶向细胞递送策略扩展到更适用的干细胞类型,即自体 iPS-EC(诱导多能内皮干细胞);避免未来转化和/或临床研究中可能出现的细胞排斥问题,并增强组织修复的功效。我们将描述静脉注射保护作用的机制。在实验性血管或心脏损伤的大鼠中施用过表达 IL8RA 和 IL8RB 的成人 EC 或 iPS-EC。我们假设过度表达IL8受体的成体EC或iPS-EC将模仿中性粒细胞的行为,其靶向并粘附于受损组织(例如受损动脉的腔内表面和外膜),并且这样做将与中性粒细胞浸润竞争并抑制中性粒细胞浸润,并减弱随后的炎症反应以及对组织的结构和功能损伤。该提案的目的是:1) 生成过度表达中性粒细胞白细胞介素 8 (IL8) 受体基因(IL8RA 和 IL8RB)的诱导多能内皮干细胞 (iPS-EC),用于将靶向细胞递送至受损的血管和心脏组织。2) 检验靶向递送过度表达中性粒细胞 IL8 的 iPS-EC 或成人 EC 的假设 受体(IL8RA 和/或 IL8RB)促进腔内血管损伤后动脉的结构和功能恢复。 3) 检验以下假设:靶向递送 iPS-EC 或过度表达中性粒细胞 IL8RA 和 IL8RB 的成人 EC 可促进实验诱导的心肌梗死 (MI) 后左心室 (LV) 的结构和功能恢复。结果 拟议的研究意义重大,因为它们有望为心血管损伤的治疗干预提供创新策略。此外,预计该结果将从根本上推动细胞治疗领域的发展,提供一种无创且具有成本效益的治疗方式。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Yiu-Fai Chen其他文献

Yiu-Fai Chen的其他文献

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{{ truncateString('Yiu-Fai Chen', 18)}}的其他基金

Targeted Delivery of iPS-Endothelial Cells for the Repair of Cardiovascular Injur
iPS 内皮细胞的靶向递送用于修复心血管损伤
  • 批准号:
    9036433
  • 财政年份:
    2013
  • 资助金额:
    $ 34.97万
  • 项目类别:
Targeted Delivery of iPS-Endothelial Cells for the Repair of Cardiovascular Injur
iPS 内皮细胞的靶向递送用于修复心血管损伤
  • 批准号:
    8703772
  • 财政年份:
    2013
  • 资助金额:
    $ 34.97万
  • 项目类别:
ANP Modulates Cardiac Remodeling via Cardiac Fibroblasts
ANP 通过心脏成纤维细胞调节心脏重塑
  • 批准号:
    7029290
  • 财政年份:
    2006
  • 资助金额:
    $ 34.97万
  • 项目类别:
ANP Modulates Cardiac Remodeling via Cardiac Fibroblasts
ANP 通过心脏成纤维细胞调节心脏重塑
  • 批准号:
    7166067
  • 财政年份:
    2006
  • 资助金额:
    $ 34.97万
  • 项目类别:
ANP Modulates Cardiac Remodeling via Cardiac Fibroblasts
ANP 通过心脏成纤维细胞调节心脏重塑
  • 批准号:
    7533506
  • 财政年份:
    2006
  • 资助金额:
    $ 34.97万
  • 项目类别:
ANP Modulates Cardiac Remodeling via Cardiac Fibroblasts
ANP 通过心脏成纤维细胞调节心脏重塑
  • 批准号:
    7329837
  • 财政年份:
    2006
  • 资助金额:
    $ 34.97万
  • 项目类别:
ENDOTHELIN AND RECEPTOR GENE EXPRESSION IN HYPOXIA
缺氧时内皮素和受体基因表达
  • 批准号:
    2771341
  • 财政年份:
    1993
  • 资助金额:
    $ 34.97万
  • 项目类别:
ENDOTHELIN AND RECEPTOR GENE EXPRESSION IN HYPOXIA
缺氧时内皮素和受体基因表达
  • 批准号:
    6389276
  • 财政年份:
    1993
  • 资助金额:
    $ 34.97万
  • 项目类别:
ENDOTHELIN AND RECEPTOR GENE EXPRESSION IN HYPOXIA
缺氧时内皮素和受体基因表达
  • 批准号:
    3369158
  • 财政年份:
    1993
  • 资助金额:
    $ 34.97万
  • 项目类别:
ENDOTHELIN AND RECEPTOR GENE EXPRESSION IN HYPOXIA
缺氧时内皮素和受体基因表达
  • 批准号:
    2487337
  • 财政年份:
    1993
  • 资助金额:
    $ 34.97万
  • 项目类别:

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