Effects of Diabetes of the Multiscale Mechanical Behavior of Clot Structures

描述（由申请人提供）：已知糖尿病患者表现出显著不同的促凝血活性特性，使其处于各种血栓性疾病和心血管疾病的较高风险中。血栓前事件在2型糖尿病患者中很常见，并且已显示出明显影响凝血级联反应，并最终影响凝块结构。实验研究试图阐明糖尿病患者和非糖尿病患者血栓形成之间的联系和差异，以及由于凝血级联反应的变化导致的疾病进展。该领域的一个具体问题是缺乏可用的定量数学和机械模型，其阐明了促血栓形成活性和糖尿病的关联，以及凝块结构如何机械地改变。另一个问题在于以下事实：缺乏在分子、细胞和组织水平上可用的定量方法，以在这些长度尺度上机械地评估糖尿病1）与正常患者相比如何产生显著不同的凝块结构2）产生不同的机械性质，这可能促进糖尿病发展和进展，导致心血管疾病。事实上，实验室数据显示，那些有血栓前事件倾向的人， 糖尿病和最终的心血管疾病，但关于这些现象的联系还有很多未知数。如果获得国家心脏，肺和血液研究所（NHLBI）指导职业发展奖，以促进教师多样性K 01奖，申请人将开发定量方法来解决分子和微观尺度力学如何因糖尿病而改变，并导致凝块中独特的机械性能差异，与正常患者相比。在分子尺度上，申请人的研究重点将是确定纤维蛋白（原）在生理相关条件下在不同加载条件下的行为。这将涉及开发新的方法来确定蛋白质在张力，弯曲，剪切和静水压力下的机械行为，使用粗粒度的分子动力学系统。已知2型糖尿病患者表现出独特的生理特性，因此将开发新的分子动力学（MD）程序，以比较/对比正常和改变（模拟糖尿病）条件下纤维蛋白（原）的机械行为。已经开发了一些定量模型来确定纤维蛋白原和其他单个ECM分子在张力下的机械行为;然而，它们旨在复制原子力显微镜（AFM）拉伸行为，并且大多数不具有生理相关性。此外，目前的实验技术和模型缺乏了解疾病发展和进展的适用性。利用所提出的实验和机械模型，申请人计划阐明力（即来自与细胞和环境的接触）如何影响纤维蛋白凝块的机械行为和结构， 正常和糖尿病生理环境。在微观水平上，申请人将结合联合收割机MD模拟结果以确定总体平均力学行为，并将其应用于开发正常和异常（糖尿病患者的特征）血栓的微观力学模型。为了突出血栓形成和糖尿病改变的联系，该模型将包括诸如红细胞的聚集效应和改变的细胞机械行为的实现。未来，我们的目标是将这些分子和细胞模型联合收割机组合成一个统一的多尺度模型，以阐明血栓形成前行为、改变的凝块结构和糖尿病/心血管疾病进展之间的联系。这些实验和计算研究工作也可以揭示其他机械现象，这些现象是由于疾病患者（如癌症患者）凝血活性的异常而产生的。 (End摘要）

DESCRIPTION (provided by applicant): Patients with diabetes have been known to exhibit markedly different properties of procoagulant activity, placing them at a higher risk for various thrombotic disorders and cardiovascular disease. Prothrombotic events are common in patients with type 2 diabetes and have been shown to distinctively affect the coagulation cascade, and ultimately the clot structure. Experimental studies have attempted to elucidate the connections and differences between thrombosis in patients with and without diabetes, and the progression of the disease due to changes in the coagulation cascade. One specific problem in the field is with the lack of available quantitative mathematical and mechanical models that clarify the association of prothrombotic activity and diabetes, and how clot structure is altered mechanically. Another problem lies in the fact that there are a lack of quantitative methods available at the molecular, cellular, and tissue levels to assess, mechanically at these length scales, how diabetes 1) engenders markedly different clot structures when compared to normal patients 2) engenders different mechanical properties, which may promote diabetes development and progression, leading to cardiovascular disease. In fact, laboratory data exists to show that those with a proclivity for prothrombotic events display a greater risk for developing diabetes and ultimately cardiovascular disease, but there are a plethora of unknowns regarding connectivity of these phenomena. If awarded the National Heart, Lung, and Blood Institute (NHLBI) Mentored Career Development Award to Promote Faculty Diversity K01 Award, the applicant will develop quantitative methods to address how molecular and micro scale mechanics are altered due to diabetes and lead to unique mechanical property differences in clots, when compared to normal patients. At the molecular scale, the applicant's research focus will be to ascertain how fibrin (ogen) behaves under different loading conditions in physiologically relevant conditions. This will involve developing new methods to determine how the proteins behave mechanically under tension, bending, shear, and hydrostatic pressure, using a coarse-grained molecular dynamics system. Patients with Type 2 diabetes are known to exhibit distinctive physiological properties, so new molecular dynamics (MD) routines will be developed to compare/contrast mechanical behavior of fibrin(ogen) in normal and altered (simulated diabetic) conditions. Some quantitative models have been developed to ascertain mechanical behavior of fibrinogen and other single ECM molecules under tension; however, they are meant to replicate atomic force microscopy (AFM) tensile behavior and most do not have physiological relevance. In addition, current experimental techniques and models lack applicability for understanding disease development and progression. With the proposed experimental and mechanical models, the applicant plans to elucidate how forces (i.e. from contact with cells and environment) affect the mechanical behavior and structure of fibrin clots in normal and diabetic physiological environments. At the micro level, the applicant will combine MD simulation results to determine ensemble average mechanical behavior and will apply this for the development of a micromechanics model of normal and abnormal (characteristic of diabetic patients) thrombi. To highlight the connections of alterations in thrombosis and diabetes, the model will include implementations such as aggregation effects and altered cellular mechanical behavior of erythrocytes. In the future, the goal is to combine these molecular and cellular models into a unified multi-scale model that will elucidate the connections between prothrombotic behavior, altered clot structure, and diabetes/cardiovascular disease progression. These experimental and computational research efforts could also shed light on other mechanical phenomena that are engendered due to aberrations of coagulant activity in patients with disease, such as those with cancer. (End of Abstract)