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

细胞外基质原纤维在纤维化过程中硬度变化和生长因子束缚中的作用

• 批准号: 1537168
• 负责人: Christopher Lemmon
• 金额: $ 37.38万
• 依托单位: Virginia Commonwealth University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1537168&HistoricalAwards=false
• 关键词: Role; Extracellular; Matrix; Fibrils; Stiffness

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.

纤维化是一种病理状况，其中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。纤维化发生在几乎每个器官中，包括肝、肾、心脏、皮肤和肺。虽然纤维化在许多疾病状态中与器官衰竭相关，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械生物学来支持该领域的基础工作。机械生物学是一个不断发展的领域，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，纤维化通过最初增加组织的硬度来进行，然后导致局部细胞产生更大的收缩力，这反过来又驱动了更坚硬的纤维化组织的组装，导致纤维化的不受控制的进展。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纤维化治疗的重要见解。虽然纤维化有组织特异性方面，但无论组织类型或疾病如何，都可以看到几个共同的主题：纤维化部位的细胞产生更大的收缩力，它们分泌增加的细胞外基质蛋白水平，并且它们具有转化生长因子-β途径的激活，这与许多疾病有关，但在伤口愈合中也至关重要。纤维化的进展驱动组织硬化，其最终扰乱组织结构并损害器官功能。研究小组假设，这些共同的事件是通过细胞驱动的细胞外基质蛋白纤连蛋白组装成弹性原纤维而整合的。这些原纤维响应于细胞产生的收缩力而组装，并具有生长因子结合位点，其以纳摩尔亲和力结合几种生长因子，包括转化生长因子-β。该研究小组将调查纤连蛋白原纤维通过增加纤维化组织中的组织硬度和通过拴系到纤连蛋白原纤维将转化生长因子β定位到细胞表面来促进纤维化的假设。该团队将通过使用微制造的柱阵列来研究这一假设，该阵列可以量化细胞产生的收缩力和纤连蛋白原纤维的组装。还将开发一种新的工具来量化体外组装的细胞外基质的刚度。