Complement C1q Function in Allogeneic Transplantation

描述(由申请人提供)：这份修订后的建议书描述了一项为期5年的移植生物学学术生涯发展培训计划。首席研究员已经完成了移植生物学方面的研究。该项目将为研究人员提供资源，以扩展他的研究技能，发展成为移植免疫学的独立研究人员。 大卫·L·珀金斯，医学博士，博士将指导首席研究员的科学发展。珀金斯博士是一名有20年研究经验的知名研究员，他的同事们都投身于学术事业。该计划将包括格雷戈里·L·斯塔尔(Gregory L.Stahl)的协助，他是一名具有补充性专业知识的博士。一个由受人尊敬的医学科学家组成的咨询委员会将通过提供科学和职业建议来为调查人员提供建议。 假设是：移植物C1q通过树突状细胞为受体T细胞适应性同种免疫反应提供关键的激活触发器，介导排斥反应。 研究将集中在补体成分C1q在移植排斥反应中的作用。珀金斯博士实验室的首席研究员最近的研究表明，缺乏ClQ的移植物移植物存活时间延长。具体目标包括：1)供者移植物中C1q缺乏是否会降低受者T细胞反应？通过将转基因GFP小鼠体内细胞转运应用于C1q缺失的小鼠心脏移植模型，我们将测定C1q缺陷移植物的效应功能、激活、细胞因子的产生以及CD4T细胞和CDS T细胞的调节。2)C1q是否调节移植后树突状细胞的激活和成熟？在有无移植物C1q的小鼠心脏移植中，利用转基因GFP小鼠体内细胞转运的模型，我们将确定C1q是否是树突状细胞激活和成熟的关键成分。这项提议的地点是布里格姆和妇女医院；为内科科学家的培训提供了良好的环境和既定的记录。长期目标是培养一位在移植免疫学领域取得成功的内科科学家。

DESCRIPTION (provided by applicant): This revised proposal describes a 5-year training program for the development of an academic career in transplantation biology. The principal investigator has completed a research fellowship in transplantation biology. This program will afford the investigator resources to expand his research skills to develop into an independent investigator in transplantation immunology. David L. Perkins, M.D., Ph.D. will mentor the principal investigator's scientific development. Dr. Perkins is an established investigator with 20 years of research experience whose fellows have gone on to academic careers. The program will include the assistance of Gregory L. Stahl, PhD with expertise in Complement. An advisory committee of respected medical scientist will advise the investigator by providing scientific and career advice. The hypothesis is: Graft C1q provides crucial activating triggers via dendritic cells for the recipient T cell adaptive alloimmune response that mediates rejection. Research will focus on the role of Complement component C1q in transplantation graft rejection. Recent work by the Principal Investigator in Dr. Perkins's laboratory shows prolonged graft survival in Clq deficient transplants. The specific aims include: 1) Does C1q deficiency in the donor graft decrease recipient T cell responses? By application of in vivo cell trafficking via transgenic GFP mice to a murine model of heart transplantation in the absence of graft C1q, we will determine the effector function, activation, cytokine production and regulation of CD4 and CDS T cells infiltrating C1q deficient allografts. 2) Does C1q modulate dendritic cell activation and maturation following transplantation? Using a model of in vivo cell trafficking via transgenic GFP mice in murine heart transplantation in the presence or absence of graft C1q, we will determine if C1q is crucial component of the activation and maturation of dendritic cells. The location for this proposal, the Brigham and Women's hospital; provides an excellent setting and an established track record for the training of physician-scientists. The long-term goal is to train a physician-scientist that will succeed in the field of transplantation immunology.