Cellular and Molecular Studies of Bone Marrow Transplant

描述（由申请人提供）：本项目拨款（PPG）的总体目标是探索同种异体骨髓移植（BMT）的细胞和分子机制，并为血液系统恶性肿瘤患者的新治疗策略提供转化研究平台。移植物抗宿主病（GVHD）仍然是异体骨髓移植后发病和死亡的主要原因，并阻碍了这种根治性治疗在癌症患者中的广泛应用；因此，整个BMT领域的长期目标是开发新的策略，将移植物抗白血病（GVL）效应从GVHD中分离出来。该PPG通过：1)探索GVHD的细胞和分子机制；2)通过将这些机制见解应用于BMT患者的I/II期临床试验，作为转化研究平台。因此，这些研究的意义在于它们有可能为癌症患者，特别是那些血液恶性肿瘤患者提供新的治疗方法。该PPG的主要主题是在不去除供体移植物中的T细胞的情况下调节供体对异体宿主组织的免疫反应。GVHD中细胞因子失调的主题以多种方式发展，并统一了整个PPG，增加了项目领导者之间的合作和互动，并提供了多种协同作用的机会。PPG由三个项目和两个核心组成：

DESCRIPTION (provided by applicant): The overall goal of this program project grant (PPG) is to explore the cellular and molecular mechanisms of allogeneic bone marrow transplantation (BMT) and to serve as a translational research platform for novel therapeutic strategies for patients with hematologic malignancies. Graft versus host disease (GVHD) remains a major cause of morbility and mortality after allogeneic BMT and prevents this curative therapy from wider application in cancer patients; thus a long term goal for the entire area of BMT is to develop new strategies to separate a beneficial graft versus leukemia (GVL) effect GVL from GVHD. This PPG contributes to that goal by: 1) exploring the cellular and molecular mechanisms of GVHD; and 2) functioning as a translational research platform by applying these mechanistic insights in Phase I/II clinical trials in BMT patients. The significance o f these studies therefore Iies in their potential to lead to novel therapies for cancer patients, particularly those with hematologic malignancies. The major theme of this PPG is the modulation of donor immune responses to allogeneic host tissues without removal of T cells from the donor graft. This theme of cytokine dysregulation in GVHD develops in several ways and unifies the entire PPG increasing collaborations and interactions among project leaders and provides multiple opportunities for synergy. The PPG consists of three projects and two cores: Regulation of Premature Keratinocyte Apoptosis in GVHD Cytokine Modulation Strategies in Clinical AIIogeneic BMT Core A Administration and Biostatistics Core B Skin Analysis and Epidermal Engineering Core C Proteomic and Genomic Analyses