Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments

炎症对造血系统 JAK2 突变体进化的影响：数学模型和实验

基本信息

批准号：
10630923
负责人：
Angela Goffredo Fleischman
金额：
$ 53.4万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-30 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630923
关键词：
Acceleration Acute Acute Myelocytic Leukemia Aspirin Benign Biological Assay Biological Models Blood coagulation Cell Lineage Cells Chronic Clinical Clinical Trials Collaborations Complex Computing Methodologies Cues Data Development Disease Disease Progression Dose Early treatment Evolution Future Goals Growth Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Inflammation Inflammatory Intervention JAK2 gene Kinetics Laboratories Mathematics Measures Mediating Modality Modeling Mus Mutation Myelofibrosis Myelogenous Myeloproliferative disease Outcome Patients Pharmaceutical Preparations Population Process Production Publishing Research Risk Risk Reduction Sampling Schedule Stimulus Survival Rate Testing Therapeutic Therapeutic Intervention Translating Treatment Protocols Work alternative treatment cell type design drug discovery effective therapy experimental study improved outcome in silico in vivo inhibitor mathematical model mouse model mutant new therapeutic target novel novel therapeutics predictive modeling pressure response symptom management targeted treatment therapeutic evaluation therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F), which leads to excessive production of myeloid lineage cells. Patients with early stage MPN can spontaneously progress to myelofibrosis, a more aggressive stage of the disease with an average survival rate of two years. Moreover, MPN patients have a significant risk of developing acute myeloid leukemia (AML). The traditional approach to therapy in MPN is simply to reduce the risk of blood clots with aspirin, manage symptoms, and observe for progression of the disease. Therapeutic intervention is focused on patients with late stage disease, mostly due to the lack of currently available therapies that halt progression. There is thus a need for interventions that impact disease progression in MPN. Preliminary work by the laboratory of Dr. Fleischman, in collaboration with mathematical modelers Komarova and Wodarz, has shown that inflammation can accelerate the growth rate of JAK2V617F mutant cells relative to JAK2WT cells, and that this can potentially have a variety of consequences for the evolution of mutant cells at homeostasis. This suggests the possibility of a new treatment modality for early stage MPN, in which the evolutionary fate of the JAK2V617F mutants is altered and disease progression is delayed or halted. The overall goal of this proposal is to investigate how this can be achieved. In Aim 1, experiments are proposed that document the dynamics of JAK2WT and JAK2V617F mutant cells in isolation with and without inflammation for the purposes of model construction and parameterization. We will also interrogate the intracellular mechanisms responsible for the differential response of JAK2V617F mutants to inflammation. In Aim 2 we will perform experiments in which JAK2WT and JAK2V617F mutant cells are combined in mouse models with and without inflammation. This will quantify how the number of mutants influence the kinetic parameters of wild- type cells, which is important because we know that mutants themselves can increase inflammation and hence alter the dynamics. In Aim 3 we will measure how a panel of existing drugs impact the kinetic parameters of cells and use our model to predict combinations and dosing schedules that will lead to diminution of the mutant cells. Many treatment scenarios (in sequence and in combination) will be explored, and the most promising therapeutic approaches predicted by the model will be tested experimentally. This can identify better and currently unknown ways in which to utilize existing drugs. On a more exploratory level, the validated mathematical model can suggest which parameter(s) to target in which ways to make treatment more efficient than can be currently done. This information would facilitate development of future treatments and guide drug discovery and could be translated into a future clinical trial.

项目概要/摘要骨髓增生性肿瘤（MPN）是一种血液系统恶性肿瘤，其特征是骨髓增生性肿瘤的克隆性生长具有体细胞获得性突变的造血细胞最常见的是 JAK2 (JAK2V617F)，这会导致骨髓谱系细胞过度产生。早期 MPN 患者可自发进展为骨髓纤维化是一种更具侵袭性的疾病阶段，平均存活率为两年。而且， MPN 患者罹患急性髓系白血病 (AML) 的风险很高。传统的方法 MPN 的治疗只是用阿司匹林降低血栓风险、控制症状并观察疾病的进展。治疗干预主要针对晚期疾病的患者，主要是由于目前缺乏阻止进展的疗法。因此，需要采取影响的干预措施 MPN 的疾病进展。 Fleischman 博士实验室与以下机构合作进行的初步工作数学模型家 Komarova 和 Wodarz 证明，炎症可以加速细胞的生长速度。 JAK2V617F 突变细胞相对于 JAK2WT 细胞，这可能会对突变细胞在稳态下的进化。这表明有可能为早期治疗提供新的治疗方式 MPN 阶段，其中 JAK2V617F 突变体的进化命运发生改变，疾病进展被延迟或停止。该提案的总体目标是研究如何实现这一目标。在目标 1 中，实验是提出记录 JAK2WT 和 JAK2V617F 突变细胞在分离和不分离的情况下的动力学炎症用于模型构建和参数化的目的。我们还将询问负责 JAK2V617F 突变体对炎症差异反应的细胞内机制。瞄准 2 我们将进行实验，其中 JAK2WT 和 JAK2V617F 突变细胞在小鼠模型中组合并且没有炎症。这将量化突变体的数量如何影响野生动物的动力学参数。型细胞，这很重要，因为我们知道突变体本身可以增加炎症，因此改变动态。在目标 3 中，我们将测量一组现有药物如何影响细胞的动力学参数并使用我们的模型来预测将导致突变细胞减少的组合和给药方案。将探索许多治疗方案（顺序和组合），并且最有希望的治疗方案模型预测的方法将通过实验进行测试。这可以更好地识别当前未知的利用现有药物的方式。在更具探索性的层面上，经过验证的数学模型可以建议以哪些方式针对哪些参数，以使治疗比目前的治疗更有效。这些信息将有助于未来治疗方法的开发并指导药物发现，并且可以转化为未来的临床试验。