PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas

计划项目资助：生发中心 B 细胞淋巴瘤的分子靶点

• 批准号: 7920581
• 负责人: Margaret A Shipp
• 金额: $ 106.18万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920581
• 关键词: PROGRAM; PROJECT; GRANT; Molecular; Targets

Germinal center (GC) B-cell lymphomas are clinically and genetically heterogeneous disorders. The incidence of the most common GC B-cell lymphomas has increased dramatically in recent years, with a 50% rise in the last generation. The participants of this PO1 believe that additional major breakthroughs in these increasingly common diseases will require a more complete understanding of critical underlying pathogenetic events. For this reason, we propose to address the following hypotheses in this competitive renewal application: 1) defects in DMA damage repair and deregulated immunoglobulin gene rearrangement predispose to oncogenic translocations and the development of lymphomas (F. Alt, Project 1); 2) tonic signaling via the B-cell receptor (BCR) pathway and constitutive activation of the canonical and alternative NFicB pathways increases the survival of GC B-cell lymphomas (K. Rajewsky, Project 2); 3) deregulated expression of the essential GC transcription factor, BCL6, promotes the development of certain large B-cell lymphomas (R. Dalla-Favera, Project 3); 4) specific subtypes of large B-cell lymphoma have unique pathogenetic mechanisms and, likely, rational therapeutic targets (M. Shipp, Project 4); and 5) components of deregulated apoptotic and transcriptional programs in GC B-cell lymphomas can be targeted using a novel chemical strategy termed hydrocarbon stapling (L. Walensky, Project 5). The proposed projects rely heavily on input of and collaboration with investigators in the following Cores: DMA Microarray/Bioinformatics (T. Golub, Core A), Hematopathology (J. Aster, Core B), Biostatistics/Clinical Trials (D. Neuberg/A. Freedman, Core C) and Administration (M. Shipp/K. Rajewsky, Core D). In this PO1, we will utilize carefully designed murine models of GC B-cell lymphomas and highly informative primary human tumors and cell lines to define the most important molecular events in these diseases. Our long-term goal is to identify predisposing factors and molecular bases for the development of GC B-cell lymphomas, improve the diagnosis of specific entities, refine our prognostic assessments and credential rational targets for more effective and specific therapeutic intervention.

生殖中心（GC）B细胞淋巴瘤在临床和遗传上是异质性疾病。这 近年来，最常见的GC B细胞淋巴瘤的发病率显着增加，为50％ 上一代上升。该po1的参与者认为，其中的其他重大突破 越来越常见的疾病将需要对关键的潜在病原体有更全面的理解 事件。因此，我们建议在此竞争性更新应用中解决以下假设：1）DMA损伤修复缺陷和放松管制的免疫球蛋白基因重排易感性易受致癌易位的易位和淋巴瘤的发展（F. Alt，Project 1）； 2）通过B细胞受体（BCR）途径的滋补信号传导以及规范和替代NFICB途径的本构激活增加了GC B细胞淋巴瘤的存活率（K. Rajewsky，Project 2）； 3）基本GC转录因子Bcl6的表达促进了某些大型B细胞的发展 淋巴瘤（R. Dalla-Favera，项目3）； 4）大B细胞淋巴瘤的特定亚型具有独特的致病机制，并且可能是理性的治疗靶标（M. Shipp，项目4）； 5）可以使用称为碳氢化合物固定剂的新型化学策略来靶向GC B细胞淋巴瘤中不受管制的凋亡和转录程序的成分（L. Walensky，项目5）。拟议的项目在很大程度上依赖于与研究人员在以下核心中与研究人员的合作：DMA微阵列/生物信息学（T. Golub，核心A），血肿学（J. Aster，Core B），生物统计学/临床试验（D. Neuberg/A。Freedman，Core C）和给药（M. Shipp/K。Rajewsky，Core D）。在此PO1中，我们将利用精心设计的GC B细胞淋巴瘤的鼠模型以及信息丰富的原发性人类肿瘤和细胞系来定义这些疾病中最重要的分子事件。我们的长期目标是确定诱人的因素 和分子碱，用于开发GC B细胞淋巴瘤，改善特定实体的诊断，完善我们的预后评估和凭证合理靶标，以进行更有效和特定的治疗干预措施。