Improving cell therapy using L-selectin homing.

使用 L-选择素归巢改善细胞治疗。

• 批准号: 7139964
• 负责人: KAREN A WESTERMAN
• 金额: $ 12.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-11 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139964
• 关键词: adhesions; muscle; selectins

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.

应聘者：首席调查员凯伦·韦斯特曼博士，在布里格姆妇女医院麻醉科当了两年的讲师。在此之前，我在一家“初创”基因治疗公司担任了5-6年的高级科学家，设计慢病毒载体系统。在这里，我请求5年的指导研究时间，以便从行业环境过渡到学术环境。这段指导时间将使我成为一名R01资助的独立研究员，并扩大我对基因治疗的知识，包括肌肉生物学、细胞贩运和血管粘连。为了完成提出的具体目标，我选择了肌肉生物学专家保罗·艾伦博士作为我的赞助人，以及一个由肖恩·科尔根博士和弗朗西斯·卢辛斯卡斯博士组成的咨询委员会，前者擅长细胞贩运，后者擅长血管黏附和细胞间连接。 环境：这项研究将在世界级科学社区的环境中进行，拥有最好的临床研究和基础科学(布里格姆和妇女医院/哈佛医学院)。 研究：在这里，我建议通过在移植细胞表面瞬时表达黏附分子L-选择素来改进用于肌肉疾病(如肌营养不良症)的细胞疗法，以促进这些细胞的归巢和向损伤部位的迁移。具体目的包括：1.利用慢病毒载体在三种细胞系中表达L-选择素。2.体外实验检测L-选择素工程细胞的黏附和跨内皮迁移能力。3.动脉内移植L-选择素工程细胞在α-肌糖缺陷小鼠体内的归巢和迁移。预期的结果是，瞬时表达L-选择素将增加这些细胞的归巢和跨内皮细胞向肌肉损伤部位的迁移。这项研究可以极大地改进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更可用的细胞类型打开大门。 相关性：使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损肌肉的归巢。在此，我建议在治疗性供体细胞的表面表达L-选择素，这是一种负责白细胞归巢到损伤部位的细胞表面黏附分子，以促进这些细胞归巢和迁移到患病肌肉。