Mathematical Model of Parotid Acinar Differentiation

腮腺腺泡分化的数学模型

• 批准号: 7686722
• 负责人: DOUGLAS S DARLING
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686722
• 关键词: Acinar Cell; Address; Algorithms; American; Biological Response Modifier Therapy; Biology; Cell Differentiation process; Computing Methodologies; Confidence Intervals; Coupled; Data; Development; Differentiation Antigens; Embryo; Equation; Foundations; Functional disorder; Gene Expression; Gene Proteins; Gene Targeting; Gene Transfer; Genes; Genomics; Goals; Histologic; MicroRNAs; Microarray Analysis; Modeling; Molecular; Muscle; Natural regeneration; Neurons; Newborn Infant; Oral; Output; Parotid Gland; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Procedures; Process; Publications; RNA; Radiation therapy; Rattus; Regulation; Regulatory Pathway; Research; Reverse Transcriptase Polymerase Chain Reaction; Salivary; Salivary Glands; Serous; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Small Interfering RNA; Source; Statistical Models; Symptoms; Syndrome; System; Systems Biology; Testing; Time; Tissues; Transfection; Validation; Variant; Western Blotting; Work; Xerostomia; cell type; expectation; gene therapy; laser capture microdissection; mathematical model; new technology; parotid cell; predictive modeling; prototype; research study; response; restoration; salivary acinar cell; salivary cell; transcription factor

DESCRIPTION (provided by applicant): The long term goal of the proposed project is to define the development of signaling networks that induce differentiation of cells into mature salivary serous acinar cells to allow gene therapy approaches to regenerating or replacing salivary tissue in patients. Millions of patients suffer loss of salivary gland function due to Sj"gren's syndrome or radiation therapy. Understanding the differentiation of salivary cells is a necessary step to enable the restoration of diseased or destroyed parotid salivary tissue. Previous work has described terminal differentiation of acinar cells histologically, and by characterizing the expression of markers of differentiation, but has not used genomics-level approaches, or mathematical models, to define regulatory pathways. The primary goal of the current application is to develop formal mathematical and statistical models that will identify networks which cause terminal differentiation of parotid acinar cells. The dynamic mathematical models will serve to generate hypotheses which will be tested, and the model will be repeatedly refined by the incorporation of new data. This application is in response to the RFA "A Systems Approach to Salivary Gland Biology." Our overall hypothesis for these studies is that a mathematical model can identify key regulatory pathways that control parotid acinar cell differentiation. Specific Aim 1 will use Laser Capture Microdissection (LCM) to obtain RNA from embryonic and newborn rat parotid acinar cells for microarray analysis of the patterns of gene expression across the period of differentiation. A coupled Ordinary Differential Equation (ODE) model will be created to describe the hypothetical interactions that direct the process of differentiation. The hypotheses will be tested, and the ODE model refined, by a combination of RT-PCR, IHC, and Western blots. Since microRNAs are important regulators of development, Specific Aim 2 will define the expression of microRNAs in acinar cells, and the pattern of changes during differentiation. There are currently no publications describing microRNAs in the parotid tissue. The results will be used to revise the mathematical model of differentiation. Specific Aim 3 will create a statistical algorithm to validate and revise the ODE model by defining the sources of bias and variation as well as by assessing the model's predictive power overall, and in its various sub-modules. This will allow confidence intervals to be associated with different pathways within the ODE model. Specific Aim 4 will use the ODE model to make hypotheses about specific pathways regulating gene expression in the parotid acinar cells. These hypotheses will be tested by transfection and transduction experiments, and the results shall be used to refine and validate the mathematical model. This systems biology approach should identify molecular pathways that drive cytodifferentiation of parotid acinar cells. Project Narrative: The overall goal of this research is to define the molecular mechanisms which control differentiation of cells into secretory salivary acinar cells. This addresses the needs of millions of Americans who suffer from salivary gland dysfunction due to Sj"gren's Syndrome, radiation therapy, or xerostomia due to essential medications. This research is a necessary foundation for developing new technologies such as gene transfer therapy and biologics for treating or alleviating the oral symptoms of xerostomia.

描述（由申请人提供）：拟议项目的长期目标是定义信号网络的发展，这些信号网络诱导细胞分化为成熟的唾液浆液性浆液腺泡细胞，以允许基因治疗方法在患者的患者中再生或替代唾液组织。由于SJ“ Gren的综合征或放射治疗，数百万患者遭受了唾液腺功能丧失。了解唾液细胞的区分是使能够恢复患病或破坏的腮腺唾液组织的必要步骤。先前的工作已经描述了腺泡细胞的终末差异化，并未通过组织学上的模型来表征，但通过不同的方法来表征，并且通过抑制了基因的表达，是基因学的表达。监管途径。数学模型可以识别控制腮腺腺泡细胞分化的关键调节途径。特定的目标1将使用激光捕获显微解剖（LCM）从胚胎和新生大鼠腮腺细胞中获取RNA，以在分化期间对基因表达模式进行微阵列分析。将创建一个耦合的普通微分方程（ODE）模型，以描述指导分化过程的假设相互作用。将测试假设，并通过RT-PCR，IHC和Western印迹的组合进行了测试。由于microRNA是发育的重要调节因子，因此特定的目标2将定义腺泡细胞中microRNA的表达以及分化过程中变化的模式。当前没有出版物在腮腺组织中描述microRNA。结果将用于修改分化的数学模型。特定的目标3将创建一种统计算法，通过定义偏差和变异的来源以及评估模型的总体预测能力及其各种子模型来验证和修改ODE模型。这将允许置信区间与ODE模型中的不同途径相关联。特定的目标4将使用ode模型对调节腮腺腺泡细胞中基因表达的特定途径进行假设。这些假设将通过转染和转导实验进行测试，结果应用于完善和验证数学模型。该系统生物学方法应确定驱动腮腺腺泡细胞细胞二分化的分子途径。项目叙述：这项研究的总体目标是定义将细胞分化为分泌唾液腺泡细胞的分子机制。这解决了由于SJ“ Gren's综合征，放射疗法或静脉疾病，由于基本药物而导致的数百万美国人的需求。这项研究是开发基因转移疗法和生物学等新技术的必要基础，例如治疗或减轻Xerostomia的口服症状。