Liver Regeneration in the Transplant Setting

描述(由申请人提供)：终末期肝病患者数量的增加导致等待移植的人数迅速增加，并加大了扩大供者池和成人至成人活体供肝(LD)肝移植的努力。LD和死亡供者(DD)移植物之间的根本差异与对缺血损伤的促炎反应的不同程度以及移植物再生的需要有关。在恢复和再生期间，肝脏必须保持代谢和合成动态平衡，如果不能，移植物将表现出不同程度的功能障碍。虽然在啮齿动物中已经定义了详细的肝损伤和再生模型，但关于人类肝脏如何启动移植后恢复和再生机制的分子细节仍未明确。我们的第一个目标是确定和验证与LD肝移植物与DD肝移植物相比与恢复相关的分子通路。我们推测，早期的分子促炎和再生图谱可能是诊断和预测随后移植肾功能的指标。质的和量的不能启动和支持分子恢复途径的进展将导致一系列的肝移植功能障碍。这一目标将利用高密度DNA微阵列来识别通过临床结果数据与成功的肝再生和移植物恢复相关的基因表达谱。第二个目的是确定供者和受者临床变量与异体移植物恢复途径的成功启动和进展的相互关系。我们的假设是，特定的临床条件可能导致促炎反应的强度，影响其消退，影响细胞周期激活和随后的再生，并在同种异体移植物的代谢途径上呈现超负荷。在给定的临床条件下，移植肝功能的临床表现可以通过早期和随后的肝活检中促炎症和再生途径的基因表达谱来诊断和预测。我们的假设将在DD和LD肝移植的背景下作为正在进行的NIDDK多中心成人对成人活体供肝移植(A2ALL)联盟的辅助研究进行验证。这项前瞻性队列研究将用于招募患者和跟踪临床结果。这项研究的结果可用于肝移植后即刻临床情况的诊断和处理。了解移植物恢复的机制生物学和肝再生的途径将为设计预防损伤和促进恢复和再生的治疗方式提供重要数据。

DESCRIPTION (provided by applicant): The increase in the number of patients with end stage liver disease has led to rapid growth of the waitlist for transplantation and increased efforts to enlarge the donor pool with and adult-to-adult living donor (LD) liver transplantation. Fundamental differences between LD and deceased donor (DD) grafts are related to the differential magnitude of the proinflammatory response to ischemic injury, and the need for graft regeneration. During recovery and regeneration the liver must maintain metabolic and synthetic homeostasis, and if unable, the graft will express various degree of dysfunction. Although detailed models of liver injury and regeneration have been defined in rodents, the molecular specifics of how a human liver initiates mechanisms of recovery and regeneration following transplantation have yet to be clearly defined. Our first Aim is to determine and validate the molecular pathways that associated with the recovery within LD liver grafts in comparison to DD grafts. We hypothesize that early molecular proinflammatory and regeneration profiles may be diagnostic and predictive of subsequent graft function. Qualitative and quantitative failure to initiate and support the progression of molecular pathways of recovery will result in a spectrum of liver graft dysfunction. This Aim will utilize high density DNA microarrays to identify gene expression profiles linked through clinical outcome data to successful liver regeneration and graft recovery. The second Aim intends to determine the interrelation of donor and recipient clinical variables with the successful initiation and progression of recovery pathways in the allograft. Our hypothesis is that specific clinical conditions may contribute to the intensity of the proinflammatory response, impact on its resolution, affect cell cycle activation and subsequent regeneration, and present an overload on metabolic pathways in the allograft. The clinical expression of graft function under a given clinical condition may be diagnosed and predicted by gene expression profiles of proinflammatory and regenerative pathways in early and subsequent liver biopsies. Our hypothesis will be tested in the setting of DD and LD liver transplantation as an Ancillary study to the ongoing NIDDK multi-center Adult to Adult Living Donor Liver Transplant (A2ALL) consortium. This prospective cohort study will be used to recruit patients and follow clinical outcomes. The results of this study may be used for the diagnosis and management of clinical conditions in the immediate post liver transplant period. Understanding the mechanistic biology of graft recovery and pathways of liver regeneration will provide important data for designing treatment modalities that will prevent injury and enhance recovery and regeneration.