Improving cell therapy using L-selectin homing

描述（由申请人提供）：候选人：主要研究者，Dr. Karen Westerman，在Brigham and Women's Hospital的麻醉科担任了2年的讲师。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，以实现从行业到学术环境的过渡。这段指导时间将使我成为一名R01资助的独立研究者，并扩大我在基因治疗方面的知识，包括肌肉生物学、细胞运输和血管粘附。为了完成我提出的具体目标，我选择了肌肉生物学专家保罗·艾伦博士作为我的赞助人，并成立了一个咨询委员会，该委员会由肖恩·科尔根博士组成，他的专长是细胞运输，弗朗西斯·卢辛斯卡斯博士的专长是血管粘附和细胞间连接。

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.