Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症信号通路的内源异质性

基本信息

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
项目类别：
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

项目摘要

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.

癌症经典地建模为具有癌基因或肿瘤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，表观构想甚至内源性这些基因表达水平的变化可能足以脱离增殖和凋亡途径并驱动肿瘤发生。因此，可能存在其起源和维持的癌症正常途径的非加工扰动。在这个项目中，我们专注于慢性淋巴细胞性白血病（CLL），这是一种淋巴增生性疾病的特征通过在细胞周期的G0/G1期间捕获的成熟B淋巴细胞的克隆膨胀。迄今为止，那里尚无赋予显性阳性或显性负面的Mutafion，会激活信号调节因子将考虑对凋亡的抗性和CLL中B细胞增殖的增殖。不同的信号传导组件的表达（例如CD和ZAP70的上调）用于预测临床前景对于CLL患者，但对它们与生长失调和疾病的相关性的了解有限进展。该研究项目的目的是研究维持增殖的B细胞信号传导的异质性和 CLL的凋亡。为此，我们将介绍一个结合理论的系统生物学平台用实验的B细胞信号传导（在抗原，细胞因子或其他激活下）建模对单一主细胞的测量。更具体地说，我们计划依靠B细胞的自然异质性（在CLL的Pafients或健康个体中），以绘制CLL疾病状态的变异性。我们将发展一个神属性生化模型，以识别B细胞信号传导中的关键信号调节剂。我们还将应用新的在单细胞水平上将B细胞反应性与表达水平相关的实验方法这些关键的信号调节器。一定，我们旨在引入单个细胞的多元参数在人群中（从标记到功能响应），以更好地表征CLL表型并提供新的考虑到CLL B细胞的可变性，治疗方法的方法。