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Improving cell therapy using L-selectin homing

利用 L-选择素归巢改善细胞治疗

基本信息

批准号：
7454968
负责人：
KAREN A WESTERMAN
金额：
$ 12.89万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/7454968
关键词：
Adhesions Advisory Committees Anesthesia Department, Hospital Animals Anterior Autologous Basic Science Biological Assay Biology Blood Blood Vessels Bone Marrow Bone Marrow Stem Cell CD34 gene CXCR4 Receptors Cell Adhesion Cell Adhesion Molecules Cell Therapy Cell Transplantation Cell Transplants Cell surface Cells Cellular biology Class Clinical Research Communities Condition Distant Endothelial Cells Environment Female Fluorescence Funding Gelatinase A Gelatinase B Green Fluorescent Proteins Heart Hematopoietic stem cells Homing Hospitals Human ITGB2 gene Immunofluorescence Immunologic In Vitro Industry Inflammation Injection of therapeutic agent Injury Intercellular Junctions Intra-Arterial Injections Knowledge L-Selectin Lentivirus Vector Leukocytes Liver MMP2 gene MMP9 gene Matrix Metalloproteinases Measures Mentors Migration Assay Monitor Mus Muscle Muscle satellite cell Muscular Dystrophies Myoblasts Myopathy Play Polymerase Chain Reaction Population Property Research Research Personnel Respiratory Diaphragm Role S-Phase Fraction Sarcoglycans Sea Senior Scientist Site Spleen Stem cells Stromal Cell-Derived Factor 1 Surface System Testing Therapeutic Time Transplantation Week Western Blotting Woman base cell motility cell population study cell type cellular engineering cellular transduction chemokine day design femoral artery gene therapy improved in vitro Assay in vivo injured instructor leukocyte homing male medical schools migration monolayer satellite cell trafficking vector venule

项目摘要

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.

描述（由申请人提供）：候选人：首席研究员 Karen Westerman 博士已在布莱根妇女医院麻醉科担任讲师 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，以实现从工业环境到学术环境的过渡。这段受指导的时间将使我成为一名 R01 资助的独立研究者，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 Allen 博士作为我的赞助商，并选择了一个咨询委员会，该委员会由擅长细胞运输的 Sean Colgan 博士和擅长血管粘附和细胞间连接的 Francis Luscinskas 博士组成。环境：这项研究将在拥有最好的临床研究和基础科学的世界级科学界环境中进行（布莱根妇女医院/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粘附分子 L-选择素来改善用于治疗肌肉营养不良等肌肉疾病的细胞疗法，以增强这些细胞向损伤部位的归巢和迁移。具体目标包括： 1.利用慢病毒载体在三个细胞群中表达L-选择素。 2.通过体外实验测试L-选择素工程细胞的粘附和跨内皮迁移。 3.通过动脉内细胞移植到α-肌聚糖缺陷小鼠体内来测试L-选择素工程细胞的归巢和迁移。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肌肉疾病治疗方法，并为开发更成熟和可用的细胞类型用于移植打开大门。相关性：用细胞疗法治疗肌肉疾病的一个主要障碍是治疗性供体细胞无法归巢到受伤的肌肉。在这里，我建议在治疗性供体细胞表面表达 L-选择素，这是一种细胞表面粘附分子，负责白细胞归巢到损伤部位，以改善这些细胞向患病肌肉的归巢和迁移。