CORE--REGULATORY MODULES IN NORMAL AND TRANSFORMED B-CELLS

核心——正常和变形 B 细胞的调节模块

• 批准号: 7676859
• 负责人: Riccardo Dalla-Favera
• 金额: $ 28.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7676859
• 关键词: Accounting; Activated B-Lymphocyte; Adoption; Affinity; Algorithms; Antibodies; Antigens; Automobile Driving; B-Cell Neoplasm; B-Lymphocytes; BCL6 gene; Behavioral; Biological; Biological Process; Biomedical Research; Cell Line; Cells; Charge; Class; Collection; Communities; Computer software; Data; Data Set; Database Management Systems; Databases; Development; Diagnosis; Documentation; Educational Activities; Educational Materials; Engineered Gene; Engineering; Gene Cluster; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Programming; Genetic Structures; Genomics; Goals; Human; Human Resources; Immune response; In Vitro; Internet; Literature; Maintenance; Malignant Neoplasms; Mediating; Normal Cell; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Physiological; Play; Policies; Population; Proto-Oncogenes; Reaction; Research; Research Infrastructure; Research Personnel; Research Proposals; Resources; Role; Secure; Security; Services; Staging; Structure; Structure of germinal center of lymph node; System; Training; Tumor-Derived; Work; base; computer center; data mining; repository; tool; tumor

The goal of this research proposal is to discover modular control structures (genetic modules), within pathways that coordinate the germinal center (GC) reaction in B cells, and to elucidate their disregulation in GC-derived tumors. The GC reaction of antigen-activated B-lymphocytes is the key biological process for the selection of B cells producing antibodies with high affinity for antigens. As such, the GC represents a key structure for the development of physiologic antibody-mediated immune responses. Furthermore, GC B-cells are involved in the pathogenesis of B cell related cancers, which include a heterogeneous group of malignancies, representing together the 5th most common class of tumors in humans. We have assembled a large collection (>300) of gene expression profile data from different B cell populations including: 1) normal cells representing the main stages of GC development; 2) panels of tumors representing the main subtypes of GC-derived malignancies; and 3) B cell lines experimentally manipulated in vitro to reflect single-gene alterations found in human tumors. Using this data set in combination with new reverse-engineering and gene clustering algorithms developed by the MAGNet Center investigators, we will discover the genetic modules that orchestrate the GC reaction, especially those differentially expressed in normal vs. tumor B cells. In particular, we propose to investigate the sub-networks that involve two proto-oncogenes: BCL6 (a gene playing an important role in the coordination of the genetic programs leading to the GC reaction) and c-MYC (a gene coexpressed with BCL6 only in tumors).

该研究建议的目的是在协调B细胞中生发中心反应（GC）反应的途径内发现模块化控制结构（遗传模块），并阐明其在GC衍生的肿瘤中的脱离。抗原激活的B淋巴细胞的GC反应是选择产生对抗原高亲和力的抗体的B细胞选择的关键生物学过程。因此，GC代表了生理抗体介导的免疫反应发展的关键结构。此外，GC B细胞参与了与B细胞相关的癌症的发病机理，其中包括异质性恶性肿瘤，代表 共同是人类中第五类最常见的肿瘤。我们已经组装了来自不同B细胞群体的基因表达谱数据（> 300），包括：1）代表GC发育主要阶段的正常细胞； 2）代表GC衍生恶性肿瘤主要亚型的肿瘤面板； 3）B细胞系在体外进行了实验操纵，以反映人类肿瘤中发现的单基因改变。使用这些数据集与磁铁中心研究者开发的新的反向工程和基因聚类算法结合使用，我们将发现策略策划GC反应的遗传模块，尤其是那些在正常肿瘤B细胞中差异表达的算法。特别是，我们建议研究涉及两种原始基因的子网络：bcl6（一种播放的基因 在导致GC反应的遗传程序的配位中的重要作用）和C-MYC（仅在肿瘤中与Bcl6共表达的基因）。