Computational Models of the Human Cell Cycle to Reveal Disease Mechanism and Inform Treatment

人类细胞周期的计算模型揭示疾病机制并为治疗提供信息

基本信息

批准号：
10033514
负责人：
Jeremy Purvis
金额：
$ 30.71万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10033514
关键词：
Abnormal Cell Activity Cycles Behavior CCNE1 gene Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Differentiation process Cell Proliferation Cell division Cell model Cells Chemicals Chromatin Clinical Treatment Clinical Trials Collaborations Combined Modality Therapy Computer Analysis Computer Models Coupling Cues Cyclin D1 Cyclin-Dependent Kinases DNA DNA Binding DNA Damage DNA Repair DNA Repair Inhibition DNA biosynthesis Data Disease Down-Regulation Embryonic Development Endoderm Epithelial Cells Eye Family Future G2 Phase Generations Genetic Genetic Transcription Geometry Goals Growth Growth Factor Receptors Human Image Image Analysis Immunofluorescence Immunologic In Vitro Inherited Joints KRAS2 gene Knowledge Learning Link Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Messenger RNA Mitosis Mitotic Modeling Modernization Molecular Mothers Mutate Mutation Network-based Oncogenes Oncogenic Organ PI3K/AKT Pancreas Pathway interactions Pharmaceutical Preparations Pharmacology Physicians Pluripotent Stem Cells Process Proliferating Protein p53 Protocols documentation Publications RAS Family Gene RAS genes Radiation Radiation Induced DNA Damage Radiation Oncology Radiation therapy Recording of previous events Refractory Research Resolution Retina S Phase Scheme Scientist Signal Transduction Stress Testing Therapeutic Time Tissues cancer therapy cell type cellular imaging chemotherapy chromatin immunoprecipitation clinically relevant convolutional neural network daughter cell design epithelium regeneration expectation extracellular gene product genetic manipulation human disease human embryonic stem cell human model human stem cells human tissue individualized medicine induced pluripotent stem cell insight paracrine pluripotency predicting response predictive modeling response small molecule small molecule inhibitor stem cells targeted treatment therapeutic DNA transmission process treatment response

项目摘要

PROJECT SUMMARY / ABSTRACT The overall goal of this project is to develop computational models that predict how the human cell cycle responds to clinically-relevant perturbations such as radiotherapy, targeted therapy, oncogenic mutation, and directed differentiation. These models will fill a significant void in our understanding of the mechanisms underlying the initiation, progression, and treatment of diseases that involve abnormal cell proliferation. Our approach is to use quantitative single-cell imaging to measure the molecular states of proliferating cells and to integrate these data into predictive modeling frameworks. We have assembled a cross-institutional team comprising a computational biologist, two cell biologists, and a physician scientist with specialization in radiation oncology. The team has a strong and productive history of collaboration with six joint publications to date. Aim 1 investigates the mechanism by which retinal epithelial cells respond to radiation-induced DNA damage during S phase to execute G2 arrest. Time-lapse imaging and deterministic modeling will predict: how the response to DNA damage is delayed until the S/G2 transition; how a small-molecule inhibitor of DNA repair—currently involved in clinical trial—intensifies the arrest response; and how loss of the tumor suppressor p53 renders cells refractory to combination therapy. Aim 2 asks how pancreatic epithelial cells with mutations in KRAS escape permanent cell cycle arrest. We will use high-content imaging to profile multiple signaling activities in single cells expressing oncogenic KRAS. These data will be used to construct a manifold representation of cell cycle progression that spans a two-week time course of oncogenic KRAS-mediated transformation. Computational analysis of the manifold’s geometry will identify molecular branching points in G1 that govern the proliferation/arrest decision in pancreatic cells, and we will validate these predictions through small molecules and genetic manipulation. Aim 3 tests the hypothesis that human embryonic stem cells inherit cell-cycle-specific gene products (specifically, G1 regulators) from the previous G2 phase to promote pluripotency in daughter cells. We will combine mitosis-specific chromatin profiling with convolutional neural network-based image analysis to identify the mechanisms by which stem cells sustain rapid proliferation and pluripotency over multiple cell-cycle generations. Each aim yields both basic and applied knowledge, providing fundamental insights into cell cycle progression under perturbation and generating specific, molecular predictions to inform new treatment schemes. With an eye toward the future, predictive models of the human cell cycle will enable patient-specific treatments for diseases that are driven by abnormal cell proliferation.

项目摘要 /摘要该项目的总体目标是开发计算模型，以预测人类细胞周期的方式对临床上相关的扰动的反应，例如放疗，靶向治疗，致癌突变和定向分化。这些模型将填补我们对机制的理解的重要空隙涉及异常细胞增殖的疾病的倡议，进展和治疗的基础。我们的方法是使用定量单细胞成像来测量增殖细胞的分子状态和至将这些数据集成到预测建模框架中。我们组建了一个跨机构的团队强迫一名计算生物学家，两名细胞生物学家和一名具有专业化的物理科学家辐射肿瘤学。该团队与六个联合出版物的合作历史有很强的产品历史日期。 AIM 1研究了仍然对辐射诱导的DNA反应的机制在S阶段执行G2逮捕的损坏。延时成像和确定性建模将预测：对DNA损伤的反应延迟到S/G2转变。小分子如何DNA的抑制剂维修 - 虽然参与了临床试验 - 降低了逮捕反应；以及肿瘤的损失抑制剂p53使细胞难以合并治疗。 AIM 2询问胰腺上皮细胞如何 KRAS中的突变逃脱了永久性细胞周期停滞。我们将使用高内感成像来概要多个表达致癌性KRA的单细胞中的信号传导活性。这些数据将用于构建多种细胞周期进程的表示，跨越了为期两周的致癌性KRAS介导的时间过程转型。歧管几何形状的计算分析将确定分子分支点控制胰腺细胞增殖/逮捕决定的G1，我们将验证这些预测通过小分子和基因操纵。 AIM 3检验了人类胚胎茎的假设细胞从上一个G2相遗传细胞周期特异性基因产物（特别是G1调节剂）促进子细胞中的多能性。我们将结合有丝分裂特异性染色质分析与卷积基于神经网络的图像分析以识别干细胞维持快速增殖的机制和多能在多个细胞周期世代上。每个目标都会产生基本知识和应用知识，提供对细胞周期进展的基本见解，并产生特定，分子预测为新的治疗方案提供信息。着眼于未来，预测模型人类细胞周期将使患者特异性治疗由异常细胞驱动的疾病增殖。