Modeling and Analysis of the Flagellar Length Control System

鞭毛长度控制系统的建模与分析

• 批准号: 8257907
• 负责人: Wallace Marshall
• 金额: $ 22.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/8257907
• 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

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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Cilia are motile structures that drive fluid flows and sense chemical signals. Patients with defects in cilia suffer from a range of debilitating symptoms including hydrocephalus and polycystic kidney disease, in some cases as a result of abnormally short or long cilia. Our study will reveal how genes could alter the length of these structures to ensure normal function.

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提出了许多挑战，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尚未回答的问题。我们专注于真核生物鞭毛作为一个简化的，一维的大小控制问题，便于定量测量。我们已经构建了一个粗粒度的模型长度控制方面的营业额和运输的鞭毛组件。初步的数据，我们定量分析鞭毛内运输和鞭毛成分的合成，使我们重新评估的简单模型。基于这些初步结果，我们建议开发一个新的集成模型的长度控制，将考虑到一系列建议的定量测量的运输和前体合成在活细胞中，使用绿色衣原体作为模型系统。通过将前体合成途径的动力系统建模和鞭毛内运输的随机建模相结合，我们将开发一种可以做出新预测的模型，特别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，以探测活细胞中长度控制系统的缩放、波动和动态。我们将利用衣原体的遗传能力，通过在改变长度的定义基因中的突变体中重复测量和模型回归，使我们能够将模型参数与分子途径和组分联系起来。我们期望，通过完成我们的目标，有一个第一个完全预测模型的细胞大小控制系统，我们希望将作为一个范例，系统级的细胞结构动力学分析。 公共卫生关系： 纤毛是驱动流体流动和感知化学信号的能动结构。纤毛缺陷的患者患有一系列衰弱症状，包括脑积水和多囊肾病，在某些情况下是由于纤毛异常短或长。我们的研究将揭示基因如何改变这些结构的长度以确保正常功能。