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TBA
Specifically, we have on-going projects in the following areas:
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We are currently investigating how the residence time of bone marrow-derived cells affects microvascular remodeling in a murine dorsal skinfold window chamber, and the molecular mechanism of this effect. Specifically, we are investigating how the prolonged presence of these cells, accomplished using sodium alginate encapsulation, influences microvascular diameter and new small vessel/capillary growth. Collective network information can be integrated to determine how the delivered cells impact whole tissue function. In addition to evaluating whole network adaptation, this study allows us the unique opportunity to investigate how bone marrow-derived cells impact venous remodeling, a generally unexplored area in microvascular research, yet one that may be a significant and specific response to the various inflammatory states which elicit bone marrow-derived cell recruitment.
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Smooth muscle myosin heavy chain (SMMHC) is the only known definitive mark of mature SM. However other markers that are also expressed by cardiac and/or skeletal muscle include smooth muscle 22 alpha (SM22a), calponin and smooth muscle alpha actin (SMaA). Though all of these proteins are involved in contraction, SMaA specifically has been identified as a mechanosensitive protein in fibroblasts, participating in stress fibers only under tension. There are a multitude of experimental approaches to study the role of tension in cell and tissue culture systems, including static strain devices. Another approach is to arrange extracellular matrix (ECM) proteins on a substrate to guide and limit cell shape/extension. This approach uses methods adopted from semiconductor chip fabrication called microcontact printing. We hypothesize that changes in cell tension, guided by ECM composition and arrangement, elicit a rhoA dependent actin reorganization necessary for epithelial to mesenchymal transformation and subsequent SM differentiation from embryonic precursors. We are exploring this hypothesis by testing two known SM embryonic precursor models, the mouse proepicardial cell explant model and the A404 line (subclone of P19).
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Bone marrow derived cells have been shown to play a supportive role in vascular growth. When their presence in hypoxic muscle tissue is increased, the amount of angiogenesis also increases, even when no incorporation into the vasculature is observed. To examine their indirect contributions through growth factor release, we have developed a chimeric mouse model with PDGF-BB -/- bone marrow, and are measuring the effects of this growth factor's absence on hypoxia-mediated angiogenesis in the mouse spinotrapezius muscle. Concurrently, we are developing an agent-based simulation to model possible mechanisms describing the effects of the paracrine contributions of these cells during angiogenesis.
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Type 2 diabetes (DM2) is currently one of the leading causes of death of adults in the United States and is characterized by insulin resistance and impaired glucose tolerance. Recent research suggests that onset and progression of the disease may be closely related to early problems in the skeletal muscle microvasculature, a major site for glucose delivery. There have been a large number of isolated observations of alterations in the DM2 skeletal muscle microvasculature of humans and animals, including a lower capillary/myocyte ratio, endothelial dysfunction, impaired hemodynamic response to insulin, and increased arteriolar wall thickness. The lack of an integrative systems analysis, however, prevents an understanding of how these alterations affect vascular resistance and blood flow in intact microvascular networks, which is crucial in assessing the individual and additive role of each physiological alteration in glucose availability to skeletal muscle. In collaboration with Dr. Eugene Barrett, we are currently using experimental data from diabetic animals as input into a computational model to compute network flow and resistance as a function of individual microvascular alterations. We hope this will allow for a better understanding of how these microvascular alterations could individually and additively impair glucose/insulin transport to skeletal muscle in type 2 diabetes, and lead to more targeted therapeutic strategies in the future.
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