A Systems Biology Approach to Predicting Bleeding in Hemophilia

描述(由申请人提供)：近年来，在了解出血疾病的分子基础方面取得了重大进展，但出血严重程度的很大一部分变异性仍未得到解释。在这个项目中，重点放在血友病和von Willebrand病(VWD)上，在这些疾病中，观察到的出血模式的可变性不能分配给一个单一的可测量参数。血栓形成是一个复杂的、非线性的过程，在患有这些疾病的人中受到严重损害。由于它涉及凝血的大的生化途径，耦合到血小板功能和包括血液流动在内的生物物理机制，它非常适合于用系统生物学的方法进行研究。这项研究的长期目标是开发补充的计算和体外模型，根据个人血液测量的变量预测个人的出血潜力。本应用的目的是确定血友病和VWD中出血的生化和生物物理修饰物。潜在的修饰物包括血液成分、血小板属性和凝块的物理性质等变量。中心假设是 我们的计算模型包括血栓形成和血小板功能的生化途径，以及血液的流体动力学，可以确定这些疾病中出血模式的主要修饰者。这一假设是根据申请者实验室提供的初步数据提出的。提出这项研究的理由是，根据单个血浆成分预测出血的简化论方法已经失败。对导致出血的生化途径有很详细的了解，但仍不可能可靠地分配出血风险。在强大的初步数据的指导下，这一假设将通过追求三个具体目标来检验：1)开发和验证出血的计算模型；2)通过计算敏感性分析确定血友病和VWD中出血的影响因素；以及3)预测一组出血性疾病患者的临床出血。在第一个目标下，现有的血栓形成模型将被修改，以模拟出血的独特生物物理环境，其定义是将血浆蛋白和血细胞运输到多孔的血管外空间。计算模型将根据基于微流控的出血分析进行验证。在第二个目标下，计算模型将用于筛选已知的影响血栓形成的变量的大参数空间。模型中显著改变出血的参数将进行实验测试，在第三个目标中，与临床出血模式相关。这些模型还将用于预测一组使用抑制剂的血友病患者对治疗的反应。这种方法是创新的，因为它代表着与现状的新的实质性背离，即对出血的生物物理机制的关注。这项拟议的研究意义重大，因为它是一系列研究的第一步，预计最终将导致改善诊断和治疗策略，以防止各种病理类型的出血。

DESCRIPTION (provided by applicant): In recent years, significant advances in understanding the molecular basis of bleeding disorders have been made, but a large portion of the variability in bleeding severity remains unexplained. In this project, the focus is on hemophilia and von Willebrand disease (VWD), where the observed variability in bleeding patterns cannot be assigned to a single measurable parameter. Clot formation is a complex, non-linear process seriously impaired in persons with these disorders. Because it involves the large biochemical pathway of coagulation coupled to platelet function and biophysical mechanisms including blood flow, it is well suited for study with a systems biology approach. The long-term goal of this research is to develop complementary computational and in vitro models that predict an individual's bleeding potential based on variables measured from their blood. The objective in this application is to identify biochemical and biophysical modifiers of bleeding in hemophilia and VWD. Potential modifiers include variables such as the composition of blood, platelet attributes, and the physical properties of clots. The central hypothesis is that our computational models that encompass the biochemical pathways of thrombus formation and platelet function coupled to the blood's fluid dynamics can identify the primary modifiers of bleeding patterns in these disorders. This hypothesis was formulated on the basis of preliminary data produced in the applicants' laboratories. The rationale for the proposed research is that the reductionist approach to predicting bleeding based on individual plasma components has failed. There is great detailed knowledge of the biochemical pathways that contribute to bleeding, but it is still not possible to reliably assign bleeding risk. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Develop and validate computational models of bleeding; 2) Identify modifiers of bleeding in hemophilia and VWD by computational sensitivity analyses; and 3) Predict clinical bleeding in a cohort of bleeding disorder patients. Under the first aim, existing models of thrombosis will be modified to simulate the unique biophysical environment of bleeding, defined by the transport of plasma proteins and blood cells into a porous extravascular space. Computational models will be validated against a microfluidic-based bleeding assay. Under the second aim, the computational models will be used to screen the large parameter space of variables known to affect clot formation. Parameters that significantly alter bleeding in the models will be tested experimentally, and, in the third aim, correlated to clinical bleeding patterns. The models will also be used to predict th response to therapy in a cohort of hemophilia patients with inhibitors. The approach is innovative because it represents a new and substantive departure from the status quo, namely a focus on the biophysical mechanisms of bleeding. The proposed research is significant because it is the first step in a continuum of research expected to lead ultimately to improved diagnosis and therapeutic strategies to prevent bleeding across a wide range of pathologies.