Stem Cell Transplantation following Myocardial Infarct in Rats

描述（由申请人提供）：本计划书描述了一个为期两年的强化训练和干细胞培养实践经验的职业提升计划，这将为重新指导首席研究员正在进行的移植研究提供基础，以研究人类胚胎干细胞来源的心肌细胞在心脏内注射到梗死大鼠心脏后的存活。该培训计划将为首席研究员在导师Gay Crooks博士和Robert Kloner博士的指导下进入干细胞生物学领域提供机会。他是干细胞研究领域公认的领导者。她是干细胞项目主任，也是洛杉矶儿童医院和南加州大学的儿科教授。她在造血领域享有盛名，因其在干细胞研究领域的贡献而备受尊敬，并在她的实验室培养了许多博士后研究员和学生。在好撒玛利亚医院心脏研究所主任、心肌细胞再生领域的领导者罗伯特·克洛纳博士的共同指导下，拟议的培训计划进一步得到加强。一个由著名科学家组成的咨询委员会将提供科学指导，并根据他们与本申请中提出的研究直接相关的专业知识被选中。提出的研究将探讨间充质干细胞中细胞保护基因的过度表达是否会提高共移植心肌细胞的存活和功能。将鉴定移植到梗死大鼠心脏的人心肌细胞中与凋亡、炎症、细胞保护基因表达和血管生成相关的早期基因表达变化。具体目的包括：1)评估hesc来源的心肌细胞与过表达HO-1的间充质干细胞联合或不联合移植到梗死大鼠心脏后的心肌细胞存活和功能。通过生物发光成像监测心肌细胞的长期存活，通过血流动力学测量和左室血管造影监测心肌细胞的功能。2)鉴定移植到梗死裸鼠心脏的人心肌细胞早期基因表达的变化。激光捕获显微解剖和聚焦路径阵列将用于研究hESC来源的心肌细胞的基因表达变化。在干细胞生物学方面的培训将为Pi的未来计划奠定基础，将她在移植耐受方面的研究扩展到研究干细胞移植后的早期免疫反应事件。（摘要结束）

DESCRIPTION (provided by applicant): This proposal describes a two year career enhancement program of intensive training and hands-on experience in stem cell culture which will provide the basis for re-directing the Principal Investigator's ongoing research in transplantation to study the survival of human embryonic stem cell-derived cardiomyocytes after intracardiac injection into infarcted rat hearts. The proposed training program will provide an opportunity for the Principal Investigator to enter the field of stem cell biology under the direction of her mentors Dr. Gay Crooks and Dr. Robert Kloner. Dr. Crooks is a recognized leader in the field of stem cell research. She is Director of the Stem Cell Program and is a Professor of Pediatrics at Childrens Hospital Los Angeles and the University of Southern California. She is renowned in the field of hematopoiesis, well-respected for her contributions to the field of stem cell research and has trained numerous postdoctoral fellows and students in her laboratory. The proposed training program is further enhanced by the co-mentorship of Dr. Robert Kloner, Director of the Heart Institute at Good Samaritan Hospital and a leader in the field of cardiomyocyte regeneration. An advisory committee of renowned scientists will provide scientific guidance, and were selected for their expertise that directly relates to the research proposed in this application. The research proposed will address whether over-expression of a cytoprotective gene in mesenchymal stem cells will enhance the survival and function of co-transplanted cardiomyocytes. Early gene expression changes associated with apoptosis, inflammation, cytoprotective gene expression and angiogenesis in human cardiomyocytes transplanted into infarcted rat hearts will be identified. The specific aims include: 1) To assess hESC-derived cardiomyocyte survival and function following transplantation of human cardiomyocytes with and without co-transplantation of mesenchymal stem cells overexpressing HO-1 into infarcted rat hearts. The long-term survival of cardiomyocytes will be monitored by bioluminescent imaging and function will be monitored by hemodynamic measurements and LV angiograms and 2) To identify early gene expression changes in human cardiomyocytes transplanted into infarcted nude rat hearts. Laser capture microdissection and focused pathway arrays will be used to study gene expression changes in hESC derived cardiomyocytes. The proposed training in stem cell biology will form the foundation for the Pi's future plans to extend her research in transplantation tolerance to studying early immune response events after stem cell transplantation. (End of Abstract)