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: 8514720
• 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/8514720
• 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活性特性，使他们处于各种血栓性疾病和心血管疾病的高风险中。血栓形成前事件在2型糖尿病患者中很常见，并已被证明能明显影响凝血级联，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血栓形成与凝血级联改变引起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力学模型来阐明血栓前活性与糖尿病的关联，以及血栓结构是如何机械地改变的。另一个问题在于，缺乏分子、细胞和组织水平的定量方法，无法在这些长度尺度上机械地评估糖尿病患者如何1)与正常患者相比产生明显不同的凝块结构2)产生不同的力学特性，这可能会促进糖尿病的发展和进展，导致心血管疾病。事实上，实验室数据表明，那些有血栓形成前事件倾向的人有更大的发展风险