Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症信号通路的内源异质性

• 批准号: 8181559
• 负责人: Gregoire Altan-Bonnet
• 金额: $ 15.03万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181559
• 关键词: Accounting; Antigens; Apoptosis; Automobile Driving; B-Lymphocytes; Biochemical; Biological Assay; Cell Cycle; Cell Survival; Cells; Cessation of life; Characteristics; Chronic Lymphocytic Leukemia; Clinical; Clonal Expansion; Computer Simulation; Custom; Data; Disease; Disease Progression; Dominant-Negative Mutation; G1 Phase; Gene Mutation; Genes; Goals; Growth; Heterogeneity; Human; In Vitro; Individual; Lymphoproliferative Disorders; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mature B-Lymphocyte; Measurement; Measures; Methodology; Modeling; Oncogenes; Pathway interactions; Patients; Phenotype; Population; Research Project Grants; Resistance; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stromal Cells; System; Systems Biology; Testing; Theoretical model; Up-Regulation; Variant; base; biochemical model; cell growth; computerized data processing; crosslink; cytokine; molecular marker; receptor; response; stem; therapeutic target; tool; tumorigenesis

Cancer is classically modeled as a malignant transformation with genetic mutation of oncogenes or tumorsuppressor genes driving uncontrolled cellular growth. However, epigenefic or even stochasfic endogenous variations in the expression levels of these genes may be sufficient to disregulate proliferation and apoptosis pathways, and drive tumorigenesis. Thus, there may exist cancers whose origin and maintenance stem from non-genefic perturbafions of normal pathways. In this project, we focus on Chronic Lymphocytic Leukemia (CLL), a lymphoproliferative disease characterized by the clonal expansion of mature B lymphocytes arrested in the G0/G1 phase of the cell cycle. To date, there is no known mutafion conferring dominant-positive or dominant negative activifies to signaling regulators that would account for the resistance to apoptosis and enhanced proliferafion of B cells in CLL. Differenfial expression of signaling components (e.g. upregulation of CDS and ZAP70) is used to predict clinical prospects for CLL patients, but there is limited understanding of their relevance to the growth dysregulation and disease progression. The goal of this research project is to study the heterogeneity of B cell signaling sustaining proliferation and apoptosis in CLL. For that purpose, we will introduce a systems biology platform that combines theoretical modeling of B cell signaling (under activation by antigens, cytokines or others) with experimental measurements on single primary cells. More specifically, we plan to rely on the natural heterogeneity of B cells (in CLL pafients or in healthy individuals), to map out the variability of CLL disease states. We will develop a theorefical biochemical model, to identify key signaling regulators in B cell signaling. We will also apply a new experimental methodology to correlate, at the single cell level, B cell responsiveness with expression levels of these key signaling regulators. Ulfimately, we aim at introducing multivariate parameters of individual cells within a population (from markers to functional response) to better characterize CLL phenotypes and offer new therapeufic approaches taking into account the variability in CLL B cells.

癌症的典型模型是癌基因或肿瘤抑制基因突变的恶性转化