CAREER: Biomechanics of the Pericellular Matrix of Fibrous Tissues

职业：纤维组织细胞周基质的生物力学

• 批准号: 1751898
• 负责人: Lin Han
• 金额: $ 50万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1751898&HistoricalAwards=false
• 关键词: CAREER; Biomechanics; Pericellular; Matrix; Fibrous

The cells in cartilage and other soft tissues are surrounded by a soft matrix of molecules that the cells produce. The response of a cell to mechanical loading depends on the mechanical properties of this matrix. If it is soft or stiff will change whether the cell is protected from mechanical loadings or whether it is not. The mechanical loads on cells are known to modify the cell's production of matrix molecules and also to change how fast the cell produces repair molecules for cartilage. The matrix, therefore, helps to control how loads on cartilage (or other soft tissues) change the cell activity. This effect of the matrix will be analyzed in this Faculty Early Career Development Program (CAREER) research project. Education and outreach activities will be integrated with the research. A new course will be developed to increase the learning of biomechanics and nanotechnology for students at Drexel. The PI will give workshops on biomechanics for Philadelphia inner city high school teachers and students, and develop a science museum exhibition display with the structure-mechanics of connective tissues as the focus. The research will add knowledge of how mechanical loading effects cartilage metabolism, a key part of understanding and preventing cartilage diseases such as osteoarthritis.This research will generate new knowledge on the biomechanics of the pericellular matrix (PCM) of fibrous tissues, to advance the understanding of fibrous tissue cell mechanotransduction. The fibrous tissue PCM is composed of porous collagen fibril network and proteoglycans (PGs). We hypothesize that this specialized PCM can attenuate cell strain under tension, and this function is mediated by its glycosaminoglycans (GAGs) on the PGs and the collagen fibril network. Using murine meniscus fibrous outer zone as the model tissue, we will test this hypothesis in two specific aims. In aim 1, we will test if removal of GAGs of the PCM reduces its compressive modulus, and thus, increases ECM-cell strain transmission and alters cell calcium signaling and metabolism under tension. In aim 2, we will alter the PCM collagen fibril structure by reducing the expression of collagen V in mice. We will test if loss of collagen V increases the PCM fibril alignment, and thus, cell strain transmission. These results will reveal the contribution of GAGs and collagen fibrils to the function of PCM in mediating cell mechanotransduction, achieving our overall goal.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

软骨和其他软组织中的细胞被细胞产生的软分子基质包围。细胞对机械载荷的响应取决于该基质的机械性质。 如果它是软的或硬的，将改变细胞是否受到保护，免受机械负荷或是否不。 已知细胞上的机械负荷会改变细胞产生基质分子的速度，也会改变细胞产生软骨修复分子的速度。因此，基质有助于控制软骨（或其他软组织）上的负荷如何改变细胞活性。 本研究将在教师早期职业发展计划（CAREER）研究项目中分析矩阵的这种效果。 教育和推广活动将与研究结合起来。一个新的课程将开发，以增加生物力学和纳米技术的学生在德雷克塞尔学习。PI将为费城市中心的高中教师和学生举办生物力学研讨会，并以结缔组织的结构力学为重点开发科学博物馆展览。该研究将增加关于机械载荷如何影响软骨代谢的知识，这是理解和预防骨关节炎等软骨疾病的关键部分。该研究将产生关于纤维组织的细胞周围基质（PCM）的生物力学的新知识，以促进对纤维组织细胞力学转导的理解。纤维组织PCM由多孔胶原纤维网络和蛋白多糖（PG）组成。我们假设这种专门的PCM可以在张力下减弱细胞株，并且这种功能是由其PG和胶原纤维网络上的糖胺聚糖（GAG）介导的。以小鼠半月板纤维外区为模型组织，我们将从两个特定的目标来检验这一假设。在目标1中，我们将测试去除PCM的GAG是否降低其压缩模量，从而增加ECM细胞应变传递并改变张力下的细胞钙信号传导和代谢。在目标2中，我们将通过减少小鼠中胶原V的表达来改变PCM胶原纤维结构。我们将测试胶原V的损失是否增加PCM原纤维排列，从而增加细胞应变传递。这些结果将揭示糖胺聚糖和胶原纤维对PCM介导细胞机械传导功能的贡献，实现我们的总体目标。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Modulated Fibrosis and Mechanosensing of Fibroblasts by SB525334 in Pediatric Subglottic Stenosis

SB525334 在儿科声门下狭窄中调节成纤维细胞的纤维化和机械传感

• DOI: 10.1002/lary.30873
• 发表时间: 2023
• 期刊: The Laryngoscope
• 作者: Ali Akbari Ghavimi, Soheila;Aronson, Matthew R.;Ghaderi, Daniel D.;Friedman, Ryan M.;Patel, Neil;Giordano, Terri;Borek, Ryan C.;Devine, Conor M.;Han, Lin;Jacobs, Ian N.
• 通讯作者: Jacobs, Ian N.