Modeling and Analysis of the Flagellar Length Control System

鞭毛长度控制系统的建模与分析

基本信息

批准号：
8464746
负责人：
Wallace Marshall
金额：
$ 21.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464746
关键词：
Accounting Affect Behavior Biological Models Caliber Cell Size Cells Cellular Structures Cellular biology Cereals Chemicals Chlamydomonas Cilia Complex Cytoplasmic Protein Data Defect Dill Ensure Equilibrium Excision Feedback Flagella Gene Mutation Genes Genetic Genetic Transcription Goals Green Algae Growth Hydrocephalus Immobilized Cells Injection of therapeutic agent Length Life Link Marshal Measurement Mediating Methods Microfluidics Microscopy Microtubules Modeling Molecular Mutation Organelles Pathway interactions Patients Polycystic Kidney Diseases Process Protein Precursors Regulation Repressor Proteins Series Signal Transduction Stochastic Processes Structure Subcellular structure Symptoms System Systems Biology Testing Time Time Series Analysis Total Internal Reflection Fluorescent Transcriptional Regulation abstracting base cell type fluid flow gene induction laser scissor models and simulation mutant novel particle predictive modeling public health relevance statistics

项目摘要

DESCRIPTION (provided by applicant): Abstract The dynamics of complex intracellular structures pose many challenges for systems biology, one of which is to understand the control systems that regulate the size of cellular structures. The question of how cells control organelle size is currently an unanswered question in cell biology. We are focusing on the eukaryotic flagellum as a simplified, one-dimensional size control problem that facilitates quantitative measurement. We have constructed a coarse-grained model for length control in terms of turnover and transport of flagellar components. Preliminary data in which we quantitatively analyze intraflagellar transport and synthesis of flagellar components has caused us to re-evaluate the simple model. Basd on these preliminary results, we propose to develop a new integrated model for length control that will take into account a series of proposed quantitative measurements of transport and precursor synthesis in living cells, using the green alga Chlamydomonas as a model system. By combining dynamical systems modeling of the precusor synthesis pathway and stochastic modeling of intraflagellar transport, we will develop a model that can make novel predictions, particularly with respect to scaling and fluctuations. We will then perform model verification and parameter estimation using new experimental methods to probe scaling, fluctuation, and dynaimcs in the length control system in living cells. We will leverage the genetic power of Chlamydomonas by repeating measurements and model regression in mutants in defined genes that alter length, allowing us to link model parameters with molecular pathways and components. We expect, by completing our aims, to have one of the first fully predictive models for a cellular size control system, which we hope will serve as a paradigm for systems-level analysis of cellular structural dynamics.

描述（由申请人提供）：摘要复杂细胞内结构的动力学对系统生物学构成了许多挑战，其中之一是了解调节细胞结构大小的控制系统。细胞如何控制细胞器大小的问题目前是细胞生物学中未解决的问题。我们将重点放在真核鞭毛上，这是一个简化的一维尺寸控制问题，可促进定量测量。我们已经构建了一个粗粒模型，以在鞭毛组件的离职和运输方面进行长度控制。我们定量分析鞭毛内运输和鞭毛组件的合成的初步数据使我们重新评估了简单的模型。在这些初步结果上，我们建议使用绿色的藻类衣原体作为模型系统，开发一个新的综合模型，以考虑到活细胞中一系列提议的运输和前体合成的定量测量。通过结合flagellar内传输的前串综合途径和随机建模的动力学系统建模，我们将开发一个模型，可以做出新的预测，尤其是在缩放和波动方面。然后，我们将使用新的实验方法进行模型验证和参数估计，以探测活细胞长度控制系统中的缩放，波动和DYNAIMC。我们将通过重复测量结果和模型回归的定义基因中的突变体的模型回归来利用衣原体的遗传能力，从而改变长度，从而使我们能够将模型参数与分子途径和组件联系起来。我们希望，通过完成我们的目标，它将拥有蜂窝大小控制系统的第一个完全预测的模型之一，我们希望该模型将作为细胞结构动力学系统级分析的范式。