Modeling to Design Treatments for Idiopathic Lung Fibrosis

项目总结 在这个国家，每年有40,000名患者被诊断为特发性肺纤维化(IPF)，这是一种进行性的 分布的肌成纤维细胞过度产生细胞外基质引起的终末期疾病 病变，或“纤维性病灶”，遍及整个肺。尽管有两种FDA批准的药物可用，但 考虑到护理标准，IPF患者的死亡率在四年内超过30%，并且没有 阻止疾病进展的药物，使诊断为IPF的美国人被判处死刑 与这种疾病一起生活。识别产生肌成纤维细胞的起源细胞是必要的 可以阻止或治愈IPF的治疗方法。基于我们的实验数据和计算模拟 研究小组，我们假设肌成纤维细胞起源于微血管周细胞(正常情况下 包裹毛细血管)，当异型周细胞-内皮相互作用被破坏时。我们进一步假设 在周细胞中对激酶介导的信号进行策略性调节可以防止周细胞向肌成纤维细胞的转变 并阻止IPF的进展。我们建议采用计算建模和实验相结合的方法进行研究 肺周细胞向肌成纤维细胞分化及肺内微血管适应的作用 敬IPF。具体地说，我们将开发一种新的基于代理的模型(ABM)，该模型结合了基于逻辑的细胞内 信令网络模拟小区行为并利用贝叶斯推理进行规则细化(目标1)， 验证ABM预测周细胞表型转变和纤维化灶出现的能力 使用博莱霉素IPF小鼠模型(AIM 2)对药物的反应，并与 临床数据，以预测可药物的激酶驱动的信号通路如何通过 周细胞和微血管的调节(目标3)。据我们所知，我们提出的研究将是第一个 将计算模型与实验相结合，研究微血管对IPF进展的贡献。在……里面 除了产生一个新的计算模型，该模型被验证为将临床前研究结果连接到 临床结果，我们希望找到针对微血管细胞的IPF新治疗方法， 以前未被发掘但可能是这种致命疾病的关键贡献者。

PROJECT SUMMARY Every year in this country 40,000 patients are diagnosed with idiopathic pulmonary fibrosis (IPF), a progressive and terminal disease caused by excessive extracellular matrix production by myofibroblasts in distributed lesions, or “fibrotic foci”, throughout the lung. Despite the availability of two FDA-approved drugs that are considered standard of care, the mortality rate for IPF patients exceeds 30% at four years, and there are no drugs that halt disease progression, making diagnosis with IPF a death sentence for over 500,000 Americans living with this disease. Identifying the cells of origin that give rise to myofibroblasts is necessary for finding treatments that can halt or cure IPF. Based on experimental data and computational simulations from our research team, we hypothesize that myofibroblasts arise from microvascular pericytes (cells that normally enwrap capillaries) when heterotypic pericyte-endothelial interactions become disrupted. We further posit that strategic modulation of kinase-mediated signaling in pericytes can prevent pericyte-to-myofibroblast transitions and halt the progression of IPF. We propose to combine computational modeling with experiments to study pericyte-to-myofibroblast differentiation and to investigate how microvessel adaptations in the lung contribute to IPF. Specifically, we will develop a new agent-based model (ABM) that incorporates logic-based intracellular signaling networks to simulate cell behaviors and leverages Bayesian inference for rule refinement (Aim 1), validate the ABM's ability to predict pericyte phenotype transitions and the emergence of fibrotic foci in response to drugs using the murine bleomycin model of IPF (Aim 2), and bridge murine experiments with clinical data in order to predict how druggable kinase-driven signaling pathways affect IPF progression via modulation of pericytes and microvessels (Aim 3). To our knowledge, our proposed studies will be the first to combine computational modeling with experiments to study microvascular contributors to IPF progression. In addition to producing a new computational model that is validated for bridging pre-clinical study results to clinical outcomes, we expect to identify new therapeutic approaches for IPF that target microvascular cells, previously underexplored but potentially critical contributors to this deadly disease.