Modeling to design optimized estrogen-specific muscle regeneration treatment

建模以设计优化的雌激素特异性肌肉再生治疗

• 批准号: 10363144
• 负责人: Silvia Salinas Blemker
• 金额: $ 20.24万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363144
• 关键词: Affect; Area; Autologous; Behavior; Biochemical; Blood Platelets; CCL2 gene; Calibration; Cell Count; Cells; Communities; Complex; Computer Models; Coupled; Data; Data Set; Disease; Embryo; Environment; Environmental Risk Factor; Estrogens; Female; Fibroblast Growth Factor; Fibroblasts; Fibrosis; Freezing; Genes; Genetic; Goals; Gonadal Steroid Hormones; Growth; Growth Factor; Hormones; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Intervention; Lead; Literature; Machine Learning; Menstrual cycle; Methods; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Myosin Heavy Chains; Natural regeneration; Outcome; Ovariectomy; Plasma; Play; Postmenopause; Prediction of Response to Therapy; Procedures; Process; Psychological reinforcement; Recovery; Role; Sex Differences; Specific qualifier value; TNF gene; Testing; Time; Tissues; Treatment outcome; Variant; Woman; Work; base; cell type; design; dosage; effective therapy; experience; experimental group; experimental study; healing; improved; in silico; in vivo; in vivo evaluation; injured; injury recovery; insight; male; muscle regeneration; novel; optimal treatments; regeneration following injury; regeneration model; response; satellite cell; sex; simulation; stem cells; tool

SUMMARY The goal of this proposal is to develop an estrogen-specific muscle regeneration agent-based model (ABM) and use it to conduct in silico experiments to identify the optimal set of growth factor interventions that improve muscle regeneration following injury. This new model will allow the field to understand how sex differences play a role in the treatment of muscle injury. It is known that current muscle injury treatments cleared by the FDA have sex- differences, which can be attributed to differences in sex hormones. Likewise, it is well documented that estrogen has a multi-faceted impact on muscle regeneration. However, while muscle regeneration models have been developed, they are based on male-only data and do not offer any insight into how sex differences alter muscle injury outcomes. These profound limitations leave the field without any tools to examine how differences in sex hormones may influence muscle damage, regeneration, and treatment outcomes. This project has two key aims that will resolve these profound limitations. The first aim will develop and validate a muscle regeneration ABM that accounts for the role of estrogen through the use of coupled in vivo and in silico experiments. This aim will be achieved by collecting data from freeze injured female mice that are receiving specified amounts of estrogen and using different subsets of the data to tune and validate the ABM. The second aim will simulate combinations of growth factors at varying levels of estrogen to identify how treatment procedures could be optimized by timing the dosage of growth factors according to estrogen levels during the menstrual cycle. Reinforcement machine learning will be used to identify the combination of growth factors, dosages, and timing that would lead to the fastest muscle recovery at varying levels of estrogen. These model-predicted optimal treatments for each estrogen level will be experimentally tested in vivo. Taken together, these aims will develop the first computational model that incorporates the effects of estrogen levels to study how they impact muscle injury treatments. This work will provide an important new understanding of sex-based differences in muscle damage, inflammation, satellite stem cell response, and overall muscle regeneration outcomes that will be crucial to developing treatments that account for these differences.

摘要 这项建议的目标是开发一种雌激素特异性肌肉再生剂模型(ABM)和 利用它进行电子计算机实验，以确定改善肌肉的最佳生长因子干预组 受伤后的再生。这一新模型将使该领域了解性别差异是如何发挥作用的 在治疗肌肉损伤方面。据了解，目前FDA批准的肌肉损伤治疗方法是性行为- 差异，这可以归因于性激素的差异。同样，有充分的证据表明，雌激素 对肌肉再生有多方面的影响。然而，尽管肌肉再生模型已经被 这些数据仅基于男性的数据，并没有提供任何关于性别差异如何改变肌肉的见解 伤害后果。这些深刻的局限性使该领域没有任何工具来研究性别差异 激素可能会影响肌肉损伤、再生和治疗结果。 该项目有两个关键目标，将解决这些深刻的限制。第一个目标将发展和 通过体内偶联作用验证肌肉再生ABM对雌激素作用的影响 以及在硅胶实验中。这一目标将通过收集冷冻损伤的雌性小鼠的数据来实现 接收指定量的雌激素，并使用数据的不同子集来调整和验证ABM。 第二个目标是模拟不同雌激素水平下的生长因子组合，以确定如何 通过根据雌激素水平选择生长因子的剂量，可以优化治疗程序。 在月经周期中。将强化机器学习用于识别增长的组合 在不同的雌激素水平下，导致肌肉恢复最快的因素、剂量和时机。这些 模型预测的每种雌激素水平的最佳治疗方法将在体内进行实验测试。加在一起， 这些目标将开发第一个结合雌激素水平影响的计算模型来研究 它们如何影响肌肉损伤的治疗。这项工作将提供一个重要的新的理解基于性别 肌肉损伤、炎症、卫星干细胞反应和整体肌肉再生的差异 这些结果将对开发解决这些差异的治疗方法至关重要。