Genetic Regulation of Lung Transplant Outcomes

描述（由申请人提供）：该奖项的总体目标是提高申请人的能力，以培训，指导和支持医生科学家的职业发展，追求转化患者为导向的研究在肺医学。这一目标将通过持续减少申请人的临床和行政责任来实现，并相应增加研究和指导活动的努力。申请人成功的研究项目正在调查肺移植物功能障碍的遗传基础，将用于为学员提供密集的研究经验，并辅之以针对每位学员的职业发展活动，包括教学课程，研究研讨会和赠款写作研讨会。尽管肺移植后移植物衰竭或排斥反应的机制尚不清楚，但我们认为环境刺激和移植物之间的持续相互作用驱动了先天性肺宿主防御的激活，并且移植肺中先天性免疫途径的激活促进了移植后移植物衰竭和排斥反应的发展。在这个项目中，我们将专门测试的假设，供体或受体先天免疫受体和信号蛋白的多态性决定患者的易感性原发性移植失败或排斥反应后肺移植。我们对人肺移植受者的初步研究支持了这一假设，这些研究表明先天免疫受体TLR4和CD14的多态性显著改变了移植失败或排斥反应的风险。我们在小鼠移植模型中的类似结果进一步支持了这一假设。我们将具体地1）确定供体或受体的先天免疫候选基因中的单核苷酸多态性（SNP）是否与原发性移植物功能障碍的发展相关，2）确定供体或受体的先天免疫候选基因中的SNP是否与急性排斥的发展相关，以及3）确定供体或受体的先天免疫候选基因中的SNP是否与1000名肺移植受试者中慢性排斥的发展相关。从这些研究中获得的知识将增强我们对先天免疫机制在移植后移植物功能障碍发展中的作用的理解，并确定新的治疗靶点以预防人肺移植后并发症。 (End摘要）

DESCRIPTION (provided by applicant): The overall goal of this award is to enhance the ability of the applicant to train, mentor and support the career development of physician scientists pursuing translational patient oriented research in pulmonary medicine. This goal will be accomplished through a sustained reduction in the applicant's clinical and administrative responsibilities with a corresponding increase in effort spent on research and mentoring activities. The applicant's successful research program which is investigating the genetic basis for pulmonary allograft dysfunction will be used to provide trainees with an intensive research experience complemented by career development activities specific to each trainee including didactic coursework, research seminars and grant writing workshops. Although the mechanisms responsible for graft failure or rejection after lung transplantation are unknown, we believe the constant interplay between environmental stimuli and the transplant allograft drives the activation of innate pulmonary host defenses and that innate immune pathway activation in the transplanted lung promotes the development of posttransplant graft failure and rejection. In this project, we will specifically test the hypothesis that polymorphisms in donor or recipient innate immune receptors and signaling proteins determine patient susceptibility to primary graft failure or rejection after lung transplantation. Support for this hypothesis is provided by our preliminary studies in human lung transplant recipients which demonstrate that polymorphisms in the innate immune receptors TLR4 and CD14 significantly alter the risk for graft failure or rejection. Further support for this hypothesis is provided by our similar results in a murine transplant model. We will specifically 1) determine if single nucleotide polymorphisms (SNPs) in innate immune candidate genes of the donor or recipient are associated with the development of primary graft dysfunction 2) determine if SNPs in innate immune candidate genes of the donor or recipient are associated with the development of acute rejection and 3) determine if SNPs in innate immune candidate genes of the donor or recipient are associated with the development of chronic rejection in 1000 lung transplant subjects. Knowledge gained from these studies will enhance our understanding of the role for innate immune mechanisms in the development of posttransplant graft dysfunction and identify novel therapeutic targets to prevent complications after human lung transplant. (End of Abstract)