Multiscale Modeling of Myelodysplastic Syndromes

骨髓增生异常综合征的多尺度建模

• 批准号: 9323833
• 负责人: Seth Joel Corey
• 金额: $ 72.97万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323833
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Age; Biological; Biological Assay; Blood; CSF3R gene; Cell Cycle Kinetics; Cell Death; Cells; Characteristics; Child; Chronic; Clinical; Clinical Management; Clinical Trials; Clonal Evolution; Clonality; Complex; Computational Biology; Computer Simulation; Cues; Cytometry; Data; Data Analyses; Data Set; Disease; Distal; Dose; Dysmyelopoietic Syndromes; Employee Strikes; Epidemiology; Event; Experimental Hematology; Exposure to; Flow Cytometry; Frequencies; Functional disorder; Gene Expression; Generations; Genes; Genetic Models; Germ-Line Mutation; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Granulopoiesis; Growth; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Heterogeneity; Host Defense; Human; Ineffective Hematopoiesis; Infection; Inherited; Instruction; Intervention; JAK2 gene; Kinetics; Knowledge; Lead; Leukocyte Elastase; Life; Light; Malignant - descriptor; Measures; Mendelian disorder; Methods; Microarray Analysis; Modeling; Molecular; Mutation; Myelogenous; Nature; Network-based; Neutropenia; Noise; Nonsense Mutation; Outcome; Pathway Analysis; Patient risk; Patients; Pattern; Pharmacology; Phenotype; Phosphoproteins; Population; Population Genetics; Probability; Publishing; RUNX1 gene; Receptor Gene; Receptor Signaling; Recombinant Granulocyte Colony Stimulating Factor; Regulator Genes; Risk; Risk Assessment; Role; Signal Pathway; Signal Transduction; Stat5 protein; Stem cells; System; Systems Analysis; Techniques; Time; Transplantation; Treatment Efficacy; Validation; accurate diagnosis; actionable mutation; base; cytopenia; data modeling; design; experimental analysis; experimental study; gene induction; genome sequencing; granulocyte; graph theory; high dimensionality; induced pluripotent stem cell; innovation; insight; mathematical model; multi-scale modeling; multidisciplinary; mutant; network models; novel; prevent; progenitor; public health relevance; response; transcription factor; whole genome

 DESCRIPTION (provided by applicant): The granulocyte is absolutely essential for host defense and survival. Its pathophysiological importance is apparent in severe congenital neutropenia (SCN). Life-threatening infections in children with SCN can be avoided through the use of recombinant granulocyte colony-stimulating factor (GCSF), which increases the number of granulocytes. However, SCN often transforms into myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). A great unresolved clinical question is: do chronic, pharmacologic doses of GCSF contribute to this transformation. Two major sets of human clinical and experimental data strongly suggest such a linkage. First, a number of epidemiological clinical trials have demonstrated a strong association between exposure to GCSF and MDS/AML. Second, mutations in the distal domain of the GCSF Receptor (GCSFR) have been isolated from 70% of patients with SCN who developed MDS/AML. Most recently, clonal evolution over ~20 years was documented in a patient with SCN who developed MDS/AML. What is very striking is that five different mutations arose in the GCSFR gene, one persisted into the AML clone but others became extinct during the course. We hypothesize that clonal evolution of an SCN sick stem cell involves perturbations in proximal and distal signaling networks triggered by a mutant GCSFR. Transition from SCNMDSAML most likely also depends on chance, hence the need for a stochastic model. To address these hypotheses through computational modeling and experimental validation, we propose the following specific aims: Aim 1) Develop and evaluate a network model to account for the dynamics of normal and aberrant GCSFR signaling effects and their interactions with mutant ELANE; and Aim 2) Estimate the number, timing, and selective advantage of mutations in granulocyte progenitors at the MDS/AML stages and develop and validate population genetics models to predict risk of transition from SCNMDSAML. To accomplish these aims, we have assembled an expert multidisciplinary team in state-of-the-art experimental hematology (high-dimensional mass cytometry, cellular barcoding, and patient-derived iPSC), computational biology, network analysis, and applied probability to develop an innovative multiscale systems analysis of how defective granulopoiesis undergoes malignant transformation. Our goal is to produce a first-generation, multi-scale model for clonal evolution of a sick blood stem cell into an unstable one. Our long-term objectives are to establish patterns of network perturbations in myeloid clonal evolution, predict patient risk fo transformation, and design measures to prevent that life-threatening event. One insight from our modeling is that we can predict when transformation to MDS can occur in patients with SCN, which could be used to optimize surveillance and clinical intervention.

 描述（由适用提供）：粒细胞对于宿主防御和生存绝对至关重要。在严重的先天性中层（SCN）中，其病理生理的重要性显而易见。通过使用重组粒细胞刺激因子（GCSF），可以避免SCN儿童的威胁生命感染，从而增加粒细胞的数量。但是，SCN通常转化为骨髓增生综合征（MDS）或急性髓样白血病（AML）。一个尚未解决的临床问题是：GCSF的慢性药理剂量是否有助于这种转变。两种主要的人类临床和实验数据强烈表明了这种联系。首先，许多流行病学临床试验表明，暴露于GCSF和MDS/AML之间存在很强的关联。其次，已从70％的SCN患者中分离出GCSF受体（GCSFR）的远端结构域中的突变。最近，在患有MDS/AML的SCN患者中记录了约20年以上的克隆进化。令人惊讶的是，GCSFR基因出现了五个不同的突变，一个持续到AML克隆中，但其他人则在课程中灭绝了。我们假设SCN病态细胞的克隆演化涉及突变GCSFR触发的近端和不同信号网络的扰动。从SCNMDSAML的过渡很可能还取决于机会，因此需要随机模型。为了通过计算建模和实验验证来解决这些假设，我们提出了以下特定目的：目标1）开发和评估网络模型，以说明正常和异常GCSFR信号效应及其与突变体的相互作用的动力学；目标2）估计MDS/AML阶段粒细胞祖细胞中突变的数量，时序和选择性优势，并开发和验证种群遗传学模型，以预测SCN→MDSaml的过渡风险。为了实现这些目标，我们组建了一支专业的多学科团队，用于最先进的实验性血液学（高维质量细胞仪，细胞核心条形码和患者衍生的IPSC），计算生物学，网络分析，并应用概率，并应用了一种创新性的多盘系统分析，对缺陷的Granululopiesis butheropiesis malignations nalignations分析。我们的目标是生产第一代，多尺度模型，以将病态干细胞的克隆进化为不稳定。我们的长期目标是在髓样克隆进化中建立网络扰动的模式，预测患者风险转化和设计措施，以防止这种威胁生命的事件。我们建模的一种见解是，我们可以预测SCN患者何时会转化为MD，这可用于优化监视和临床干预。