A Unified Model of Gene Regulatory Circuit Evolution

基因调控电路进化的统一模型

• 批准号: 8709852
• 负责人: Victor Hanson-Smith
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709852
• 关键词: Accounting; Animal Model; Award; Behavior; Biochemistry; Biological Assay; Candida; Candida albicans; Cells; Chronic; Clinic; Code; Communities; Complex; Computer Simulation; DNA; DNA Binding; Development; Devices; Evolution; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Human; Human Microbiome; Implant; Infection; Lead; Learning; Life; Light; Medical Device; Microbial Biofilms; Modeling; Molecular; Molecular Evolution; Molecular Models; Mutation; Pathway interactions; Physiological; Population; Positioning Attribute; Probability; Process; Property; Proteins; Recording of previous events; Regulator Genes; Relative (related person); Research; Simulate; Solutions; Structure; Surface; System; Techniques; Testing; Thermodynamics; Time; Training; Trees; Yeasts; abstracting; base; candida biofilm; genome sequencing; member; molecular modeling; multidisciplinary; novel; pathogen; public health relevance; reconstruction; research study; simulation; trait; transcription factor

DESCRIPTION (provided by applicant): Cells control the timing and expression levels of their genes using special regulatory genes that interact in complex circuits to activate or repress the transcription of protein-coding DNA. We have little understanding of how complex transcriptional circuits evolve. The goal of this project is to combine multiple approaches - genomics, biochemistry, molecular evolution, ancestral reconstruction, and computational modeling - to learn the evolutionary mechanisms underlying complex regulatory circuits. The applicant, Dr. Victor Hanson-Smith, will use the yeast species Candida albicans as a model organism for studying this problem. C. albicans form surface-associated biofilms on implanted medical devices in humans; device-associated biofilms serve as reservoirs for chronic infection and life-threatening illness. C. albicans control biofilm formation using a complex circuit with six master-regulator genes and thousands of downstream target genes. It is not known how biofilm formation evolved, or if the C. albicans biofilm network is one evolutionary solution among many alternatives. Dr. Hanson-Smith will study the evolution of the biofilm gene circuit using a new quantitative model that incorporates unprecedented detail about gene regulation. His approach is to learn empirically- derived parameter values for this model from molecular experimentation in C. albicans, and then use simulation studies to test models for the evolution of biofilm formation. Dr. Hanson-Smith's approach differs from many other types of evolutionary simulations as it is based on real properties of the relevant molecules involved rather the abstract parameters of gene regulation. Since this is a F32 training award, a major component of this project is the training of Dr. Hanson-Smith in the techniques of genome sequencing and assaying gene expression levels. At the end of this project, Dr. Hanson-Smith will have received outstanding training in the molecular systems governing gene regulation, and therefore - combined with his computational background -- he will be well positioned to establish and direct his own research lab. Scientifically, this project will shed light on the evolutionary pathway by which C. albicans acquired biofilm formation; it may also reveal novel ways of controlling biofilm formation in the clinic, and general principles of how future pathogens might be expected to evolve. More broadly, this project will provide a framework for understanding, and even predicting, the types of evolutionary trajectories that lead to the development of complex physiological traits across the tree of life.

描述（由申请人提供）：细胞使用特殊调控基因控制其基因的时间和表达水平，这些基因在复杂回路中相互作用以激活或抑制蛋白质编码DNA的转录。我们对复杂的转录回路是如何进化的知之甚少。这个项目的目标是结合联合收割机多种方法-基因组学，生物化学，分子进化，祖先重建和计算建模-学习复杂的调控电路的进化机制。申请人维克托汉森-史密斯博士将使用酵母菌属白色念珠菌作为研究该问题的模式生物。C.白色念珠菌在人体内植入的医疗装置上形成表面相关的生物膜;装置相关的生物膜充当慢性感染和危及生命的疾病的储存库。C.白色念珠菌使用具有六个主调节基因和数千个下游靶基因的复杂回路来控制生物膜形成。目前还不清楚生物膜的形成是如何进化的，也不知道C。白色念珠菌生物膜网络是许多备选方案中的一种进化解决方案。汉森-史密斯博士将使用一种新的定量模型研究生物膜基因电路的进化，该模型包含了有关基因调控的前所未有的细节。他的方法是从C.白色念珠菌，然后使用模拟研究来测试生物膜形成的演变模型。汉森-史密斯博士的方法不同于许多其他类型的进化模拟，因为它是基于相关分子的真实的性质，而不是基因调控的抽象参数。由于这是一个F32培训奖，该项目的一个主要组成部分是汉森-史密斯博士在基因组测序和测定基因表达水平的技术培训。在这个项目结束时，汉森-史密斯博士将在基因调控的分子系统方面接受出色的培训，因此-结合他的计算背景-他将很好地建立和指导自己的研究实验室。科学上，这个项目将揭示C。白念珠菌获得生物膜形成;它也可能揭示在临床上控制生物膜形成的新方法，以及未来病原体如何进化的一般原则。更广泛地说，该项目将提供一个框架，用于理解甚至预测导致生命树中复杂生理特征发展的进化轨迹类型。