Genomics for Transplantation: Discovery and Biomarkers

描述（由申请人提供）：该计划的首要主题是采用基因组学，蛋白质组学和遗传学的前沿技术，并严格和批判性地应用这些工具来应对移植免疫学和生物学的主要挑战。功能基因组学的这些努力旨在实现三个互补的目标：1)生物学发现，2)生物标志物发现，以及3)这些发现的翻译，以提高肾脏和心脏移植临床实践的安全性和有效性。我们所有人都相信，最好的转化医学是由最好的基础研究推动的。我们认为，对分子机制的基本生物学理解的认真努力必须由高度组织的科学家和医生团队密切合作来推动。当这种合作关系成功地将科学和医学结合在一起时，由此产生的基础但临床知情的知识可以直接转化为保护健康和征服疾病。正是这种努力使我们在上一个筹资期间所做的一切以及现在打算做的一切都具有意义。在个别项目和核心中详细介绍了许多科学和临床假设。但这个项目的核心假设是，多维功能基因组学将使我们看到在移植时触发的多种平行免疫机制之间的联系，然后随着时间的推移而进化。事实上，正是这种时间的演变决定了移植的最终临床结果。因此，如果早期损伤没有完全修复，如果由供体和受体基因决定的免疫反应是反应性的、进行性的或失调的，如果产生抗体，如果免疫抑制无效或由于任何原因不足，这些因素将驱动移植的进行性免疫/炎症破坏。我们的使命是尽量减少这种结果。为了完成这一任务，我们计划从基础生物学到临床验证的生物标志物特征，以诊断和预测移植结果。最终，我们希望创造基因组工具，使医生能够优化和个性化免疫抑制的安全性和有效性。

DESCRIPTION (provided by the applicant): The over-arching theme of this Program is taking cutting edge technologies for genomics, proteomics and genetics and applying these tools rigorously and critically to the major challenges of transplantation immunology and biology. These efforts in functional genomics are designed to accomplish three complementary objectives: 1) biological discovery, 2) biomarker discovery, and 3) translation of these discoveries to enhance the safety and efficacy of clinical practices in kidney and heart transplantation. All of us believe that the best of translational medicine is advanced by the best of basic research. We believe that serious efforts to achieve fundamental biological understanding of molecular mechanisms must be driven by highly organized teams of scientists and physicians working in close concert. When such collaborative relationships bring science and medicine together successfully, the resulting basic but clinically informed knowledge can be translated directly to preserving health and conquering disease. That effort is what gives meaning to everything we have done in the last funding period and propose to do now. There are many scientific and clinical hypotheses detailed in the individual Projects and Cores. But the central hypothesis of this Program is that multi-dimensional functional genomics will allow us to see the connections between the multiple, parallel mechanisms of immunity that are triggered at the time of a transplant and then evolve in time. In fact, it is this evolution in time that determines the ultimate clinical outcome of the transplant. Thus, if early injury is incompletely repaired, if the immune response determined by both donor and recipient genetics is reactive and progressive or dysregulated, if antibodies are generated and if immunosuppression is ineffective or inadequate for any reason, these elements will drive a progressive, immune/inflammatory destruction of the transplant. It is our mission to minimize this kind of outcome. To achieve this mission we plan to go from basic biology to biomarker signatures validated clinically for diagnosis and prediction of transplant outcomes. Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression.