Pathogenesis and Therapy of Chronic Lung Rejection

描述(申请人提供)：超过10,000个肺和心肺 移植手术已在全球范围内进行。这些程序已被证明是 对许多受助者来说非常有效；然而， 肺移植受者的死亡率显著低于肾脏、心脏、 和肝脏接受者。这在很大程度上是由于 慢性肺排斥，组织学表现为OB，临床表现为 闭塞性细支气管炎综合征(BOS)。这项提议的目标是 提高对免疫发病机制、分子诊断和 肺移植后CR的治疗。要做到这一点，我们有 组建了一支由经验丰富的调查人员组成的多学科团队 世界？S最有经验和最受尊敬的肺移植中心。建议数 该计划由四个应用创新实验的研究项目组成 解决以下三个主要差距的方法和最新技术 知识：首先，虽然同种免疫反应被普遍认为是 CR发病机制的核心，其分子机制 反应的发生仍然不清楚。项目1和项目2涉及 CR的免疫发病机制使用T细胞受体Tg小鼠其中的位置和 可以确定移植物特异性T细胞的活性。第二个主要问题 一直无法确定特定的高危接受者群体 增强免疫抑制或新疗法的潜在候选者。 项目3通过使用大规模的基因表达来解决这个问题 鉴定敏感和特异基因的微阵列(&gt；10,000个基因)技术 与CR相关的表达模式。最后，当前的治疗 主要基于加强免疫抑制治疗的方法是 在逆转受影响最严重的慢性肺排斥反应过程中无效 个人。项目4试图探索一种新的治疗方向： 基因转染法诱导呼吸道成纤维细胞的凋亡 构建，这使它们对HMG-CoA还原酶抑制剂敏感。这些项目 在本提案中，将由两个核心支持：1)管理核心 将协调行政、教育和生物统计职能 计划；2)小鼠气管移植核心将集中 与执行、收获和处理异位生物相关的专业知识 项目1、2和4中使用的小鼠气管移植。

DESCRIPTION (provided by applicant): More than 10,000 lung and heart-lung transplants have been performed worldwide. These procedures have proven to be highly effective for many recipients; however, long-term survival rates for lung recipients are considerably lower than those observed in kidney, heart, and liver recipients. This is due, in large part, to the development of chronic lung rejection, manifested histologically as OB, and clinically as bronchiolitis obliterans syndrome (BOS). The goal of this proposal is to improve understanding of the immunopathogenesis, molecular diagnosis, and therapy of CR after lung transplantation. To accomplish this, we have assembled a multidisciplinary team of experienced investigators at one of the world?s most experienced and respected lung transplant centers. The proposed Program consists of four research projects which apply innovative experimental approaches and state-of the-art technologies to address three major gaps in knowledge: First, while an alloimmune reaction is generally accepted to be central to the pathogenesis of CR, the molecular mechanisms by which this reaction occurs remain obscure. Projects 1 and 2 address the immunopathogenesis of CR use T-cell receptor Tg mice in which the location and activity of graft-specific T-cells can be identified. A second major problem has been the inability to identify a specific group of at-risk recipients as potential candidates for augmented immune suppression or novel therapeutics. Project 3 addresses this problem by using large-scale gene expression microarray (>10,000 genes) technology to identify sensitive and specific gene expression patterns associated with CR. Finally, current therapeutic approaches, based primarily on augmenting immune suppressive therapy, are ineffective in reversing the course of chronic lung rejection in most affected individuals. Project 4 seeks to explore a novel therapeutic direction: triggering apoptosis in airway fibroblasts by transfection with gene constructs, which sensitize them to HMG-CoA reductase inhibitors. The projects in this proposal will be supported by two cores: 1) An Administrative Core will coordinate administrative, educational, and biostatistical functions of the Program; and 2) a Murine Tracheal Transplant Core will concentrate expertise related to performing, harvesting, and processing the heterotopic mouse tracheal transplants used in Projects 1, 2, and 4.