Studies of Receptor Mediated Signal Transduction Processes in Mammalian Cancer Bi

描述(由申请人提供)：我描述了一种系统的方法来开发和实施新的方法，以探索基于实验数据的哺乳动物细胞外源性凋亡中受体介导的信号模型。我的重点将集中在信号事件上，从细胞表面的配体结合到线粒体外膜的通透性和最终的效应器caspase激活。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验线粒体外膜通透性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来补充这一点。将这样的模型与实验数据进行校准将是我工作的中心方面。我期待着有关细胞凋亡的新理论的发展，这将为我们提供新的研究方向。拟议工作的第二阶段将扩展模型，同样基于实验数据，检查药物对不同类型的转化细胞和未转化细胞的影响。在生物学工作的同时，我将开发工具，允许灵活处理复杂网络模型，从而促进生物学研究。将通过使用我们实验室为传播和推广项目而开发的基于语义维基的软件，特别注意模型跟踪、模型共享及其与实验的联系。在奖项的独立部分，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培训结合起来，开发出准确描述细胞环境的工具，并实施方法来减少在当前建模工作中难以获得的参数数量。我希望我的项目将对细胞凋亡信号通路的研究、对药物及其与与细胞凋亡相关的蛋白质的相互作用的理解，以及植根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。

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.