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)

PROJECT NARRATIVE The relationship between thrombosis and diabetes has been elucidated recently to ascertain what mechanisms are responsible for differences in clottability and disease development and progression. Many of these studies are being conducted to qualitatively understand the biological relationships between thrombosis and diabetes. In this study, I will develop experimental tools and mechanical/mathematical models at the molecular and cellular length scales to quantitatively ascertain the relationships between altered thrombus (clot) structure and diabetes. This is important to the field of biomedicine and biomedical engineering, in that it will help to elucidate specifically how altered clot structures in diabetes patients, due to prothrombotic events, facilitates with the progression of disease.