A Systems Biology Approach to Predicting Bleeding in Hemophilia

描述（由申请人提供）：近年来，在理解出血性疾病的分子基础方面取得了重大进展，但大部分出血严重程度的变异性仍然无法解释。在本项目中，重点关注血友病和血管性血友病（VWD），其中观察到的出血模式变异性无法分配给单个可测量参数。凝块形成是一个复杂的非线性过程，在患有这些疾病的人中严重受损。因为它涉及凝血的大的生化途径耦合到血小板功能和生物物理机制，包括血流，它非常适合用系统生物学方法研究。这项研究的长期目标是开发互补的计算和体外模型，根据从血液中测量的变量预测个体的出血潜力。本申请的目的是鉴定血友病和VWD出血的生物化学和生物物理改性剂。潜在的修饰符包括变量，如血液成分、血小板属性和凝块的物理性质。核心假设是， 我们的计算模型包括血栓形成和血小板功能的生物化学途径，以及血液的流体动力学，可以识别这些疾病中出血模式的主要调节剂。这一假设是根据申请人实验室的初步数据提出的。提出这项研究的理由是，基于单个血浆成分预测出血的简化方法已经失败。对导致出血的生化途径有非常详细的了解，但仍然不可能可靠地分配出血风险。在强有力的初步数据的指导下，将通过追求三个特定目标来检验这一假设：1）开发和验证出血的计算模型; 2）通过计算敏感性分析识别血友病和VWD中出血的修饰因子; 3）预测出血性疾病患者队列中的临床出血。根据第一个目标，现有的血栓形成模型将被修改，以模拟独特的生物物理环境的出血，血浆蛋白和血细胞的运输到一个多孔的血管外空间定义。将针对基于微流体的出血测定来验证计算模型。根据第二个目标，计算模型将用于筛选已知影响凝块形成的变量的大参数空间。将通过实验测试显著改变模型中出血的参数，并且在第三个目标中，与临床出血模式相关。该模型还将用于预测具有抑制剂的血友病患者队列中对治疗的反应。这种方法是创新的，因为它代表了一种新的和实质性的偏离现状，即专注于出血的生物物理机制。拟议的研究意义重大，因为它是一系列研究的第一步，预计最终将导致改进的诊断和治疗策略，以预防各种病理学的出血。

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.