Effects of Diabetes on the Multiscale Mechanical Behavior of Clot Structures

糖尿病对血块结构多尺度力学行为的影响

• 批准号: 8367991
• 负责人: Rodney D Averett
• 金额: $ 13.52万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367991
• 关键词: Address; Adult; Affect; American; Atomic Force Microscopy; Award; Behavior; Biological; Biological Assay; Biomedical Engineering; Cardiovascular Diseases; Cell model; Cells; Cereals; Cessation of life; Characteristics; Child; Clinical Research; Coagulants; Coagulation Process; Complex; Computer Simulation; Computing Methodologies; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Endocrinology; Environment; Erythrocytes; Event; Exhibits; Extracellular Matrix; Faculty; Fiber; Fibrin; Fibrinogen; Future; Goals; Heart Diseases; Hematology; Hydrostatic Pressure; K-Series Research Career Programs; Laboratories; Lead; Length; Light; Link; Malignant Neoplasms; Mechanics; Medical; Mentored Research Scientist Development Award; Mentors; Methods; Mind; Modeling; Molecular; Molecular Models; National Heart, Lung, and Blood Institute; Neural Network Simulation; Non-Insulin-Dependent Diabetes Mellitus; Patients; Pharmacia brand of estropipate; Physiological; Population; Prediabetes syndrome; Prevalence; Property; Proteins; Research; Research Activity; Risk; Severities; Shapes; Simulate; Stroke; Structure; System; Techniques; Thrombosis; Thrombus; Time; Tissues; United States; abstracting; cardiovascular disorder risk; career; design; diabetic; diabetic patient; high risk; mathematical model; mechanical behavior; molecular dynamics; molecular modeling; molecular scale; mortality; multi-scale modeling; novel therapeutics; predictive modeling; research study; tool; viscoelasticity

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)

描述（由申请人提供）：已知糖尿病患者表现出明显不同的促凝血活性特性，使他们面临各种血栓性疾病和心血管疾病的更高风险。血栓前事件在 2 型糖尿病患者中很常见，并且已被证明会显着影响凝血级联，并最终影响血栓结构。实验研究试图阐明糖尿病患者和非糖尿病患者的血栓形成与凝血级联变化导致的疾病进展之间的联系和差异。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来阐明血栓前活动与糖尿病的关联，以及血块结构如何机械改变。另一个问题在于，缺乏分子、细胞和组织水平上的定量方法来在这些长度尺度上机械地评估糖尿病 1) 与正常患者 2) 相比如何产生明显不同的血栓结构不同的机械性能，可能会促进糖尿病的发生和进展，导致心血管疾病。事实上，实验室数据表明，那些有血栓前事件倾向的人表现出更大的患血栓形成的风险。 糖尿病，最终是心血管疾病，但这些现象之间的联系还有很多未知数。如果获得国家心肺血液研究所 (NHLBI) 指导职业发展奖以促进教师多样性 K01 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独特的机械性能与正常患者相比，血栓的差异。在分子尺度上，申请人的研究重点将是确定纤维蛋白（原）在生理相关条件下的不同负载条件下如何表现。这将涉及开发新方法，使用粗粒度分子动力学系统来确定蛋白质在张力、弯曲、剪切和静水压力下的机械行为。众所周知，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) 程序来比较/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一 ECM 分子在张力下的机械行为；然而，它们的目的是复制原子力显微镜（AFM）拉伸行为，并且大多数不具有生理相关性。此外，当前的实验技术和模型缺乏理解疾病发生和进展的适用性。通过所提出的实验和机械模型，申请人计划阐明力（即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。 正常和糖尿病的生理环境。在微观层面上，申请人将结合MD模拟结果来确定总体平均机械行为，并将其应用于正常和异常（糖尿病患者的特征）血栓的微观力学模型的开发。为了强调血栓形成和糖尿病变化之间的联系，该模型将包括聚集效应和红细胞细胞机械行为改变等实施。未来，我们的目标是将这些分子和细胞模型结合成一个统一的多尺度模型，以阐明血栓前行为、血块结构改变和糖尿病/心血管疾病进展之间的联系。这些实验和计算研究工作还可以揭示由于疾病患者（例如癌症患者）凝血活性异常而产生的其他机械现象。 （摘要完）