Improving cell therapy using L-selectin homing

描述（由申请人提供）：候选人：主要研究者Karen Westerman博士，在Brigham妇女医院麻醉科担任讲师已有2年。在此之前，我在一家设计慢病毒载体系统的“初创”基因治疗公司担任了5-6年的高级科学家。在这里，我要求5年的指导研究时间，使从工业到学术环境的过渡。这段指导时间将使我成为R 01资助的独立调查员，并扩大我对基因治疗的知识，包括肌肉生物学，细胞运输和血管粘附。为了完成提出的具体目标，我选择了肌肉生物学专家Paul艾伦博士作为我的赞助商，以及由Sean Colgan博士和Francis Luscinskas博士组成的咨询委员会，Sean Colgan博士的专长是细胞运输，Francis Luscinskas博士的专长是血管粘附和细胞与细胞连接。 工作环境：这项研究将在世界一流的科学界环境中进行，具有最好的临床研究和基础科学（布里格姆妇女医院/哈佛医学院）。 研究：在这里，我建议改善用于治疗肌肉疾病，如肌营养不良症的细胞为基础的疗法，通过瞬时表达的粘附分子，L-选择素，在移植细胞的表面上，以增强归巢和迁移这些细胞的损伤部位。具体目标包括：1.利用慢病毒载体在三种细胞中表达L-选择素。2.体外实验检测L-选择素工程细胞的粘附和跨内皮迁移能力。3.通过动脉内细胞移植，检测L-选择素工程细胞在α-肌聚糖缺陷小鼠体内的归巢和迁移能力。预期的结果是L-选择素的瞬时表达将增加这些细胞向肌肉损伤部位的归巢和跨内皮迁移。这项研究可以大大改善基于细胞的治疗肌肉疾病的方法，并为用于移植的更发达和可用的细胞类型打开大门。 相关性：用基于细胞的疗法治疗肌肉疾病的一个主要障碍是缺乏治疗性供体细胞对受伤肌肉的归巢。在这里，我建议表达L-选择素，细胞表面粘附分子，这是负责白色血细胞归巢损伤部位，在治疗供体细胞的表面上，以改善归巢和迁移这些细胞的患病肌肉。

DESCRIPTION (provided by applicant): Candidate: The principle investigator, Dr. Karen Westerman, has been an Instructor in the Anesthesia Department at Brigham and Women's Hospital for 2 years. Prior to this I was a Senior Scientist for 5-6 years at a "start-up" gene therapy company designing lentiviral vector systems. Here I request 5 years of mentored research time to make the transition from industry to the academic environment. This mentored time will allow me to become a R01 funded independent investigator and to broaden my knowledge of gene therapy to include that of muscle biology, cell trafficking, and vascular adhesion. To complete the specific aims proposed I have chosen Dr. Paul Allen, an expert in muscle biology, as my sponsor, and an advisory committee composed of Dr. Sean Colgan who's expertise is in cell trafficking, and Dr. Francis Luscinskas who's expertise is in vascular adhesion and cell-to-cell junctions. Environment: This research will be carried out in an environment of a world-class scientific community with the best of both clinical research and basic science (Brigham and Women's Hospital/Harvard Medical School). Research: Here I propose to improve cell-based therapies used for the treatment of muscle diseases such as Muscular Dystrophy by transiently expressing an adhesion molecule, L-selectin, on the surface of transplanted cells to enhance homing and migration of these cells to sites of injury. The specific aims include: 1. To use lentiviral vectors to expression of L-selectin in three cell populations. 2. To test the adhesion and transendothelial migration of L-selectin engineered cells by in vitro assays. 3. To test the homing and migration of L-selectin engineered cells by intra-arterial cell transplantation into a -sarcoglycan deficient mice. The expected results are that transient expression of L-selectin will increase homing and transendothelial migration of these cells to sites of muscle injury. This research could substantially improve cell-based therapy for treatment of muscle disease and open the door to more developed and available cell types to be used for transplantation. Relevance: A major hurdle in treating muscle disease with cell-based therapies is the lack of homing of therapeutic donor cells to injured muscles. Here I propose to express L-selectin, a cell surface adhesion molecule which is responsible for white blood cell homing to sites of injury, on the surface of therapeutic donor cells to improve the homing and migration of these cells to the diseased muscle.