The Role of Extracellular Matrix Fibrils in Stiffness Changes and Growth Factor Tethering during Fibrosis

纤维化是一种病理状态，组织愈合以不受控制的方式进行。据估计，西方世界近一半的死亡可归因于纤维化。纤维化几乎发生在每个器官，包括肝、肾、心脏、皮肤和肺。虽然人们很好地认识到，在许多疾病状态下，纤维化与器官衰竭有关，但很少有治疗方法被证明是成功的。该奖项将通过研究纤维化的机制生物学来支持这一领域的基础工作。机械生物学是一个发展中的领域，研究人员研究细胞和组织的机械特性在疾病进展中的作用。研究小组假设，纤维化是通过最初增加组织的硬度来进行的，然后导致局部细胞产生更大的收缩力量，进而推动更多僵硬的纤维组织的组装，导致纤维化的失控进展。这项研究有可能通过研究纤维化进展背后的机械信号来发现对纤维化治疗的重要见解。虽然纤维化有组织特异性的方面，但有几个共同的主题，无论是组织类型或疾病，都可以看到：纤维化部位的细胞产生更大的收缩力量，它们分泌增加的细胞外基质蛋白水平，它们提高了转化生长因子-β途径的激活，这与许多疾病有关，但在伤口愈合中也是关键的。纤维化的进展会导致组织僵硬，最终扰乱组织结构，损害器官功能。研究小组假设，这些常见的事件是通过细胞驱动的细胞外基质蛋白纤维连接蛋白组装成弹性纤维来整合的。这些纤维是在细胞产生的收缩力量的作用下组装起来的，并具有一个生长因子结合部位，该结合部位可以结合几种生长因子，包括具有纳摩尔亲和力的转化生长因子-β。研究小组将研究纤维连接蛋白纤维通过增加纤维化组织中的组织硬度和通过与纤维连接蛋白纤维连接将转化生长因子-β定位于细胞表面来促进纤维化的假设。该团队将通过使用微型制造的柱子阵列来研究这一假说，这种柱子阵列可以量化细胞产生的收缩力量和纤维连接蛋白纤维的组装。还将开发一种新的工具来量化体外组装的细胞外基质的硬度。

Fibrosis is a pathological condition in which tissue healing proceeds in an uncontrolled manner. It has been estimated that nearly half of all deaths in the western world can be attributed to fibrosis. Fibrosis occurs in nearly every organ, including liver, kidney, heart, skin, and lung. While it is well appreciated that fibrosis is associated with organ failure in many disease states, there are few treatments that have proven successful. This award will support fundamental work in this area by studying the mechanobiology of fibrosis. Mechanobiology is a growing field in which researchers investigate the role of mechanical properties of cells and tissues in disease progression. The research team hypothesize that fibrosis proceeds by initially increasing the stiffness of the tissue, which then leads to the generation of larger contractile forces in local cells, which in turn drives the assembly of more stiff fibrotic tissue, resulting in uncontrolled progression of fibrosis. This research has the potential to discover important insights in fibrosis treatment by investigating the mechanical signaling that underlies fibrosis progression. While there are tissue-specific aspects of fibrosis, there are several common themes that are seen regardless of tissue type or disease: cells at the site of fibrosis generate larger contractile forces, they secrete increased levels of extracellular matrix proteins, and they have elevated activation of the Transforming Growth Factor-beta pathway, which is implicated in many diseases, but is also critical in wound healing. Progression of fibrosis drives tissue stiffening, which ultimately disturbs tissue structure and impairs organ function. The research team hypothesizes that these common events are integrated through cell-driven assembly of the extracellular matrix protein fibronectin into elastic fibrils. These fibrils are assembled in response to cell-generated contractile forces and possess a growth-factor binding site that binds several growth factors, including Transforming Growth Factor-beta, with nanomolar affinity. The research team will investigate the hypothesis that fibronectin fibrils facilitate fibrosis by both increasing tissue stiffness in fibrotic tissue and localizing Transforming Growth Factor-beta to the cell surface via tethering to fibronectin fibrils. The team will investigate this hypothesis through the use of microfabricated pillar arrays that can quantify both cell-generated contractile forces and assembly of fibronectin fibrils. A novel tool will also be developed to quantify the stiffness of in vitro assembled extracellular matrix.