Multiscale Modeling of Myelodysplastic Syndromes

骨髓增生异常综合征的多尺度建模

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：粒细胞对于宿主防御和生存绝对必要，其病理生理学重要性在严重先天性中性粒细胞减少症（SCN）中可以通过使用重组粒细胞集落来避免。刺激因子 (GCSF)，可增加粒细胞数量。然而，SCN 经常转化为骨髓增生异常综合征 (MDS) 或急性髓系白血病。 (AML)。一个尚未解决的临床问题是：慢性、药理学剂量的 GCSF 是否会导致这种转变。首先，大量的流行病学临床试验已经证明了这种联系。其次，最近从 70% 患有 MDS/AML 的 SCN 患者中分离出了 GCSF 受体 (GCSFR) 远端域的突变。在一名患有 MDS/AML 的 SCN 患者中记录了大约 20 年的克隆进化，非常引人注目的是 GCSFR 基因中出现了五种不同的突变，其中一种持续存在于 AML 克隆中，但其他突变在该克隆过程中消失了。 SCN 患病干细胞的进化涉及由突变 GCSFR 触发的近端和远端信号网络的扰动，从 SCNMDSAML 的转变很可能也取决于机会，因此为了通过计算建模和实验验证来解决这些假设，我们提出了以下具体目标：目标 1) 开发和评估网络模型，以解释正常和异常 GCSFR 信号传导效应的动态及其与突变体的相互作用。 ELANE；和目标 2) 估计 MDS/AML 阶段粒细胞祖细胞突变的数量、时间和选择性优势，并开发和验证遗传群体模型以预测从为了实现这些目标，我们组建了一支在最先进的实验血液学（高维质谱流式细胞仪、细胞条形码和患者来源的 iPSC）、计算生物学、网络分析方面的多学科专家团队。，并应用概率开发一种创新的多尺度系统分析，分析有缺陷的粒细胞生成如何经历恶性转化。我们的目标是产生第一代多尺度模型，用于将患病的造血干细胞克隆进化为造血干细胞。我们的长期目标是建立骨髓克隆进化中的网络扰动模式，预测患者转化的风险，并设计措施来防止这种危及生命的事件，我们的模型的一个见解是我们可以预测何时转化为不稳定的。 MDS 可能发生在 SCN 患者中，这可用于优化监测和临床干预。