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）：我描述了一种基于实验数据，探索哺乳动物细胞外源凋亡中模型受体介导的信号的新方法的系统方法。我的重点将放在从细胞表面的配体结合到线粒体外膜通透性和最终效应子caspase激活的信号传导事件。这项工作中的发现还将对分子癌细胞生物学和相关领域的原型提示 - 信号响应途径产生影响。我将使用理论方法研究不同竞争机制对线粒体外膜通透性的有效性，并与我们实验室中收集的实验数据进行补充。这种模型对实验数据的校准将是我工作的核心方面。我希望发展有关细胞凋亡的新理论，这将暗示新的研究方向。提议的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未转化细胞的影响，也基于实验数据。与生物学工作同时，我将开发工具，以灵活地处理复杂的网络模型，从而促进生物学研究。注意模型跟踪，模型共享及其与实验的联系将通过在我们的实验室中开发的基于语义Wiki的软件来特别关注该项目的传播和宣传。为了获得奖项的独立部分，我将将我新获得的癌症分子生物学知识与我的理论物理化学培训合并，以开发工具，以准确描述细胞环境并实施方法，以减少在当前建模工作中难以获得的参数数量。我希望我的项目对凋亡中信号通路的研究产生深远的影响，对药物的理解及其与与凋亡相关的蛋白质的相互作用以及植根于细胞分子癌生物学需求的工具的发展。 公共卫生相关性：我们的研究将为外在凋亡途径的调节和控制提供新的见解及其与癌症的关系。这些研究旨在统一有关细胞凋亡激活和对线粒体外膜通透性的承诺的争议。此外，还将开发出新的分析，建模和数据注释工具，这些工具将对癌症治疗产生深远的影响。