COMPUTATIONAL CELL BIOLOGY: ANALYSIS OF AUTOCRINE LOOPS

我们建议开发数学模型和计算工具，使空间分辨分析的反应和运输自分泌信号的影响。自分泌环的空间特征将在纳米（使用随机布朗动力学模拟）和微米（使用确定性反应扩散方程）的长度尺度上进行研究。我们的建模工作将自然地补充申办者小组的实验计划，该计划积极关注表皮生长因子受体（EGFR）系统中自分泌环的结合、运输、信号传导和生理方面。计算技术与EGFR实验数据的结合将增强我们对该系统的理解，该系统在癌症进展的许多方面都至关重要。研究自分泌系统的一个主要困难是它们高度局部化的性质。直接测量释放速率和扩散距离等参数极为困难。然而，这些参数决定了自分泌环的功能作用。根据最近提出的“细胞声纳”假说，自分泌生长因子的空间限制网络为细胞提供位置信息。自分泌环的局部中断（例如通过分泌的配体与细胞外基质的组分结合）将通过结合模式的局部扰动来反映，结合模式的局部扰动反过来可能被翻译成局部生理反应（例如伪足延伸的蛋白酶激活）。我们的模型将提供一个重要的定量评估的假设信号传导机制，可能是在各种正常和病理情况下操作。

We propose to develop mathematical models and computational tools enabling the spatially resolved analysis of reaction and transport effects in autocrine signaling. The spatial character of autocrine loops will be examined on the length scales of nanometers (using stochastic Brownian Dynamic simulations) and microns (using deterministic reaction-diffusion equations). Our modeling effort will naturally complement the experimental program in sponsor's group that is actively focusing on binding, trafficking, signaling and physiological aspects of autocrine loops in the Epidermal Growth Factor Receptor (EGFR) system. A combination of computational technique with experimental data available for the EGFR will enhance our understanding of the system that is critical in many aspects of cancer progression. A major difficulty with investigating autocrine systems is their highly localized nature. It is extremely difficult to directly measure parameters such as release rates, and diffusion distances. These parameters, however, determine the functional role of autocrine loops. According to the recently proposed 'cell sonar' hypothesis, spatially restricted networks of autocrine growth factors provide cells with positional information. Localized interruption of an autocrine loop (e.g. by binding of secreted ligand to components of the extracellular matrix) will be mirrored by a localized perturbation of a binding pattern that, in its turn, might be translated into a localized physiological response (e.g. protease activation of pseudopod extension). Our models will provide a critical quantitative evaluation of the hypothesized signaling mechanism that might be operative in a variety of normal and pathological contexts.