Determining disease intervention strategies using spatially resolved simulations.
Determining disease intervention strategies using spatially resolved simulations.
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DOI：
10.1371/journal.pone.0080506
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kumar V
中科院分区：
文献类型：
--
作者：
Read M;Andrews PS;Timmis J;Williams RA;Greaves RB;Sheng H;Coles M;Kumar V
由于不同组织中不同细胞类型之间复杂的相互作用决定了疾病的结果，因此预测小分子和生物疗法的功效和最佳药物递送策略具有挑战性。在这里，我们提出了一种新的方法来模拟炎症性疾病的表现和测试潜在的干预策略，在硅片上使用基于代理的计算模型。使用这种方法创建的模拟具有明确的空间和时间表示，并捕获导致病理或疾病解决方案出现的异质和随机细胞行为。为了证明这种方法，我们模拟了原型小鼠T细胞介导的自身免疫性疾病实验性自身免疫性脑脊髓炎，多发性硬化症的小鼠模型。在模拟免疫细胞动力学中，出现了神经元损伤和组织特异性病理学，与小鼠模型中发现的行为非常相似。使用校准的模拟，我们分析了T细胞受体信号传导抑制的时间和功效的变化如何导致疾病恶化或消退。所描述的技术是了解复杂炎症性疾病中细胞行为的强大新方法，允许合理设计药物干预策略，并为TCR信号传导在自身免疫性疾病进展中的作用提供了新的见解。
Predicting efficacy and optimal drug delivery strategies for small molecule and biological therapeutics is challenging due to the complex interactions between diverse cell types in different tissues that determine disease outcome. Here we present a new methodology to simulate inflammatory disease manifestation and test potential intervention strategies in silico using agent-based computational models. Simulations created using this methodology have explicit spatial and temporal representations, and capture the heterogeneous and stochastic cellular behaviours that lead to emergence of pathology or disease resolution. To demonstrate this methodology we have simulated the prototypic murine T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. In the simulation immune cell dynamics, neuronal damage and tissue specific pathology emerge, closely resembling behaviour found in the murine model. Using the calibrated simulation we have analysed how changes in the timing and efficacy of T cell receptor signalling inhibition leads to either disease exacerbation or resolution. The technology described is a powerful new method to understand cellular behaviours in complex inflammatory disease, permits rational design of drug interventional strategies and has provided new insights into the role of TCR signalling in autoimmune disease progression.
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影响因子：
3.3
作者：
Beeston, Tara;Smith, Trevor R. F.;Maricic, Igor;Tang, Xiaolei;Kumar, Vipin
通讯作者：
Kumar, Vipin
影响因子：
168.9
作者：
Sherry, Nicole;Hagopian, William;Ludvigsson, Johnny;Jain, Sunil M.;Wahlen, Jack;Ferry, Robert J., Jr.;Bode, Bruce;Aronoff, Stephen;Holland, Christopher;Carlin, David;King, Karen L.;Wilder, Ronald L.;Pillemer, Stanley;Bonvini, Ezio;Johnson, Syd;Stein, Kathryn E.;Koenig, Scott;Herold, Kevan C.;Daifotis, Anastasia G.
通讯作者：
Daifotis, Anastasia G.
影响因子：
1.6
作者：
Greaves, Richard B.;Read, Mark;Kumar, Vipin
通讯作者：
Kumar, Vipin
影响因子：
4.4
作者：
Madakamutil, LT;Maricic, I;Kumar, V
通讯作者：
Kumar, V
影响因子：
56.9
作者：
KOH, DR;FUNGLEUNG, WP;MAK, TW
通讯作者：
MAK, TW