Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症信号通路的内源异质性

• 批准号: 8377739
• 负责人: Gregoire Altan-Bonnet
• 金额: $ 42.63万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 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/8377739
• 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.

癌症被经典地建模为具有癌基因或抑癌基因基因突变的恶性转化 驱动不受控制的细胞生长的基因。然而，表观或甚至随机的内源 这些基因表达水平的变化可能足以扰乱增殖和凋亡。 途径，并推动肿瘤的发生。因此，可能存在癌症，其起源和维持源于 正常路径的非遗传性扰动。 在这个项目中，我们关注慢性淋巴细胞白血病(CLL)，这是一种以淋巴增生性疾病为特征的疾病 通过克隆扩增使成熟B淋巴细胞停滞于细胞周期的G0/G1期。到目前为止，有 目前还没有已知的突变因子向监管机构发出显性正向或显性负向激活的信号 可能与CLL中B细胞的抗凋亡和促增殖有关。不同的 信号成分的表达(例如CDS和ZAP70的上调)用于预测临床前景 对于慢性淋巴细胞性白血病患者，但对其与生长发育失调和疾病的相关性了解有限 进步。 本研究项目的目的是研究B细胞信号的异质性，以维持增殖和 慢性淋巴细胞性白血病的细胞凋亡。为此，我们将引入一个系统生物学平台，该平台结合了理论 用实验方法模拟B细胞信号(在抗原、细胞因子或其他因素激活下) 对单个原代细胞的测量。更具体地说，我们计划依靠B细胞的天然异质性 (在慢性淋巴细胞性白血病患者或健康人中)，以绘制出慢性淋巴细胞性白血病疾病状态的变异性。我们将开发一种 理论生化模型，以确定B细胞信号转导中的关键信号调节因子。我们还将应用一个新的 在单细胞水平上将B细胞反应性与表达水平相关联的实验方法 这些关键的信号调节器。最终，我们的目标是引入单个细胞的多变量参数 在群体内(从标记到功能反应)更好地表征CLL表型并提供新的 考虑到CLL B细胞的变异性的治疗方法。