MR imaging of stem cell-gene therapy of atheroscleroses

描述(由申请人提供)： 动脉粥样硬化性心血管疾病是一种独特的疾病，具有多发性、弥漫性和不同分期的斑块，可累及全身。到目前为止，对于多发性/弥漫性动脉粥样硬化的早期诊断或有效治疗，还没有成熟的方法可用。最近的研究证实，在不同的动脉粥样硬化病变模型中，骨髓细胞的迁移可以产生血管前体细胞，这些细胞位于受损的血管中，并分化为内皮细胞或平滑肌细胞。输注的造血干祖细胞(SC)被严格限制在动脉粥样硬化斑块中，从而加速再内皮化，从而减少新生内膜的形成。这一概念“斑块特异的造血干细胞运输”促使我们开发了一种新技术，使用磁共振成像来监测和指导斑块特异的干细胞介导的多发性/弥漫性动脉粥样硬化的早期诊断和治疗。 在目前的方案中，我们将开发两种新技术：(A)通过创建针对多发性/弥漫性斑块的磁性标记干细胞，对早期多发性/弥漫性动脉粥样硬化进行斑块特异性、SC介导的磁共振成像；以及(B)通过将治疗基因转导到针对多发性/弥漫性斑块的磁性标记干细胞，进行多发性/弥漫性动脉粥样硬化的MR成像引导、斑块特异性、SC介导性基因治疗。这两项新技术发展的原理将首先在一系列体外和体内实验中得到验证，使用的是供体小鼠的造血骨髓干细胞和受体小鼠的动脉粥样硬化模型，使用分子磁共振成像。随后，这两项新技术将在临床前环境中进行验证，使用临床磁共振成像下具有多个/弥漫性动脉粥样硬化的接近人类大小的尤卡坦猪模型。我们坚信，该项目的成功将为未来使用基于磁共振成像的干细胞介导的血管基因/药物疗法有效地管理人类的心血管缺血性疾病开辟新的途径。(摘要结束)

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease is a unique illness with multiply-located and diffusely-fashioned, as well as differently-staged plaques, that can involve the entire body. To date, there are no established methods available for either early diagnosis or efficient treatment of multiple/diffuse atheroscleroses. Recent studies have confirmed that the migration of bone marrow cells can give rise to vascular progenitor cells that home in the damaged vessels and differentiate into either endothelial cells or smooth muscle cells in various models of atherosclerotic lesions. The transfused hematopoietic stem-progenitor cells (SC) are strictly restricted to atherosclerotic plaques, which accelerates re-endothelialization and thereby reduces neointima formation. This concept, "plaque-specific trafficking of hematopoietic SCs," motivated us to develop a new technology using MR imaging to monitor and guide plaque-specific, stem cell-mediated early diagnosis and therapy of multiple/diffuse atheroscleroses. In the current proposal, we will develop two novel techniques: (a) plaque-specific, SC-mediated MR imaging of early multiple/diffuse atheroscleroses by creating magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques; and (b) MR imaging-guided, plaque-specific, SC-mediated gene therapy of multiple/diffuse atheroscleroses by transducing a therapeutic gene to the magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques. The principles of these two novel technical developments will be first tested and proved in a series of in vitro and in vivo experiments with hematopoietic bone marrow stem cells of donor mice and atherosclerotic models of recipient mice using molecular MR imaging. Subsequently, the two novel techniques will be validated in a preclinical setting using near human-sized Yucatan pig models with multiple/diffuse atheroscleroses under clinical MR imaging. We firmly believe that the success of this project will open up new avenues for the future efficient management of cardiovascular ischemic disorders in humans using MR imaging-based, stem cell-mediated vascular gene/drug therapy. (End of Abstract)