Chemomechanical Stimulation of Adventitial Fibroblast Remodeling of Collagen

该奖项的研究目标是使用细胞和组织培养方法以及非线性生物力学的独特组合来量化和模拟纤维状胶原的产生和交联的速度和程度，这些纤维状胶原是由外基质成纤维细胞在与动脉生物学和病理学相关的化学机械刺激下产生的。具体来说，主动脉成纤维细胞将受到三种不同类型的双轴载荷，并将其反应量化为暴露于血管内皮细胞响应血流变化而释放的两种有效的血管活性分子和两种有效的胶原酶交联剂的功能，以阐明这四种生物分子对整体组织预应力、各向异性和刚度的影响。这些反应将与主动脉平滑肌细胞的反应进行比较，以描绘这两种相关细胞类型重塑胶原蛋白能力的差异。如果成功，这项研究将产生一个独特的生长和重塑计算模型，有助于阐明在平滑肌细胞功能丧失的情况下（例如，在主动脉瘤中）动脉修复和疾病进展的机制。平滑肌细胞和成纤维细胞类似地共同促进许多其他组织的功能，包括气道、胃肠道和尿道，它们可以单独或一起用于构建组织工程结构。因此，了解这两种细胞类型对化学-机械耦合刺激的反应将具有广泛的意义。这项工作的影响将通过在不同的期刊上发表，在高级准备的本科生生物力学和生物运输教科书上，以及在IUPS生理组网站上发表。一名博士生和多名本科生将在实验和计算力学生物学方面接受独特的跨学科培训。

The research objective of this award is to use a unique combination of cell and tissue culture approaches and nonlinear biomechanics to quantify and model the rates and extents of production and cross-linking of fibrillar collagens by adventitial fibroblasts in response to chemo-mechanical stimuli that are relevant to arterial biology and pathology. Specifically, aortic fibroblasts will be subjected to three different classes of biaxial loading and their responses quantified as a function of exposure to two potent vasoactive molecules that are released by vascular endothelial cells in response to changes in blood flow and two potent enzymatic cross-linkers of collagen to elucidate effects of these four biomolecules on overall tissue pre-stress, anisotropy, and stiffness. These responses will be compared to those of aortic smooth muscle cells to delineate differences in the ability of these two allied cell types to remodel collagen. If successful, this study will yield a unique growth and remodeling computational model that should help elucidate mechanisms of arterial repair and disease progression in cases where the function of smooth muscle cells is lost (e.g., in aortic aneurysms). Smooth muscle cells and fibroblasts similarly work together to promote the function of many other tissues, including airways, the gastrointestinal tract, and the urinary tract, and they can be used separately or together in building tissue engineered constructs. Understanding responses by these two cell types to coupled chemomechanical stimulation will thus have broad implications. The impact of this work will be broadened by publishing the findings in diverse journals, in an undergraduate biomechanics and biotransport textbook that is in advanced preparation, and on the IUPS Physiome website. One Ph.D. student and multiple undergraduate researchers will receive unique interdisciplinary training in experimental and computational mechanobiology.