Studies of Receptor Mediated Signal Transduction Processes in Mammalian Cancer Bi

哺乳动物癌症中受体介导的信号转导过程的研究

• 批准号: 8111595
• 负责人: Carlos Federico Lopez
• 金额: $ 11.86万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-07 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111595
• 关键词: Apoptosis; Apoptotic; Attention; Award; Biological; Biology; Calibration; Cancer Biology; Caspase; Cell Death; Cell physiology; Cells; Cellular Structures; Cellular biology; Collaborations; Complement; Complex; Computer software; Cues; Data; Development; Environment; Equation; Event; Failure; Free Energy; Gases; Goals; HCT116 Cells; Hela Cells; Knowledge; Laboratories; Life; Ligand Binding; Link; Literature; Malignant Neoplasms; Mammalian Cell; Manuals; Measures; Mediating; Membrane; Methodology; Methods; Modeling; Modification; Molecular; Molecular Biology; Molecular Models; Molecular Structure; Molecular Target; Outer Mitochondrial Membrane; Pathway interactions; Patients; Pharmaceutical Preparations; Physical Chemistry; Plant Roots; Process; Programming Languages; Proteins; Reaction; Receptor Mediated Signal Transduction; Regulation; Research; Semantics; Signal Pathway; Signal Transduction; Staging; Statistical Mechanics; Surface; System; Systems Biology; TNFSF10 gene; Testing; Time; Training; Tumor Cell Line; Validation; Work; anticancer research; base; cancer cell; cancer therapy; career development; cell transformation; cellular imaging; chemical kinetics; computer based Semantic Analysis; data modeling; design; flexibility; improved; insight; interest; knowledge base; mathematical model; molecular modeling; neoplastic cell; network models; novel; outreach; prevent; programs; reaction rate; receptor; receptor-mediated signaling; research study; response; simulation; skills; software development; theories; tool; tool development; wiki

DESCRIPTION (provided by applicant): I describe a systems approach to develop and implement novel methods to explore model receptor-mediated signaling in extrinsic apoptosis in mammalian cells based on experimental data. My focus will be on the signaling events from ligand binding at the cellular surface to mitochondrial outer membrane permeabilization and eventual effector caspase activation. The discoveries from this work will also have an impact in prototypical cue-signal-response pathways in molecular cancer cell biology and related fields. I will examine the validity of different competing mechanisms for mitochondrial outer membrane permeabilization using theoretical approaches and complement this with experimental data collected in our laboratory. The calibration of such a model to experimental data will be central aspect of my work. I expect the development of novel theories about apoptosis which will suggest new research directions. A second stage of the proposed work will expand the models to examine the effect of drugs on transformed and non-transformed cells of different types, also based on experimental data. Concurrent with the biological work, I will develop tools that will allow for flexible treatment of complex network models thus facilitating the biological studies. Attention to model tracking, model sharing, and its connection with experiments will be given special attention through the use of semantic- Wiki based software developed in our laboratory for dissemination and outreach of the project. Toward the independent part of the award I will merge my newly acquired cancer molecular cell biology knowledge with my theoretical physical chemistry training to develop tools which accurately describe cellular environments and implement methods to reduce the number of parameters that are difficult to obtain in current modeling efforts. I expect my project to have a profound impact on the study of signaling pathways in apoptosis, the understanding of drugs and their interactions with proteins related to apoptosis, and the development of tools rooted in the needs of cell molecular cancer biology. PUBLIC HEALTH RELEVANCE: Our study will provide new insights into the regulation and control of the extrinsic apoptosis pathway and its relation to cancer. These studies aim to unify the existing controversy as to the activation of apoptosis and commitment to the mitochondrial outer membrane permeabilization. In addition, novel analytic, modeling, and data annotation tools will be developed that will have deep impact on cancer treatment.

描述（由申请人提供）：我描述了一种系统方法，用于开发和实施新方法，以基于实验数据探索哺乳动物细胞外源性细胞凋亡中模型受体介导的信号传导。我的重点是从细胞表面的配体结合到线粒体外膜透化和最终效应器半胱天冬酶激活的信号传导事件。这项工作的发现也将对分子癌细胞生物学和相关领域的典型线索-信号-反应途径产生影响。我将使用理论方法检查线粒体外膜透化的不同竞争机制的有效性，并用我们实验室收集的实验数据对此进行补充。将这样的模型与实验数据进行校准将是我工作的核心方面。我期待有关细胞凋亡的新理论的发展，这将提出新的研究方向。拟议工作的第二阶段将扩展模型，以检查药物对不同类型的转化和非转化细胞的影响，同样基于实验数据。在进行生物学工作的同时，我将开发能够灵活处理复杂网络模型的工具，从而促进生物学研究。通过使用我们实验室开发的基于语义维基的软件来传播和推广该项目，将特别关注模型跟踪、模型共享及其与实验的联系。对于该奖项的独立部分，我将把我新获得的癌症分子细胞生物学知识与我的理论物理化学训练相结合，以开发准确描述细胞环境的工具，并实施方法来减少当前建模工作中难以获得的参数数量。我希望我的项目将对细胞凋亡信号通路的研究、对药物及其与细胞凋亡相关蛋白质相互作用的理解、以及根植于细胞分子癌症生物学需求的工具的开发产生深远的影响。 公共健康相关性：我们的研究将为外源性细胞凋亡途径的调节和控制及其与癌症的关系提供新的见解。这些研究旨在统一关于细胞凋亡激活和线粒体外膜透化作用的现有争议。此外，还将开发新颖的分析、建模和数据注释工具，这将对癌症治疗产生深远的影响。