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，具有多部位和弥漫性，以及不同阶段的斑块，可以涉及整个身体。到目前为止，还没有成熟的方法可用于多发性/弥漫性动脉粥样硬化的早期诊断或有效治疗。最近的研究已经证实，骨髓细胞的迁移可以产生血管祖细胞，这些血管祖细胞在受损的血管中归巢，并在各种动脉粥样硬化病变模型中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，这加速了再内皮化，从而减少了新生内膜形成。这一概念，“斑块特异性运输造血干细胞”，促使我们开发一种新的技术，使用MR成像监测和指导斑块特异性，干细胞介导的早期诊断和治疗多发性/弥漫性动脉粥样硬化。 在目前的建议中，我们将开发两种新的技术：（a）斑块特异性，SC介导的早期多发性/弥漫性动脉粥样硬化的MR成像，通过创建磁标记的干细胞，交通/靶向特异性的多发性/弥漫性斑块;和（B）MR成像引导的，斑块特异性的，SC介导的多发性/弥漫性动脉粥样硬化的基因治疗，通过将治疗基因转导至磁标记的干细胞，专门针对多发性/弥漫性斑块。这两个新的技术发展的原则将首先测试和证明在一系列的体外和体内实验与造血骨髓干细胞的供体小鼠和动脉粥样硬化模型的受体小鼠使用分子MR成像。随后，这两种新技术将在临床前环境中使用临床MR成像下具有多发性/弥漫性动脉粥样硬化的接近人类大小的尤卡坦猪模型进行验证。我们坚信，该项目的成功将为未来使用基于MR成像的干细胞介导的血管基因/药物治疗有效管理人类心血管缺血性疾病开辟新的途径。 (End摘要）

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)