CAREER: Studying Tendon Cell Mechanobiology in the Native Tissue Environment

该学院早期职业发展（Career）基金支持研究确定肌腱内细胞的行为如何受到组织损伤的影响，以及这如何导致肌腱变性。以往的工作研究了在人工条件下肌腱细胞对不同菌株的反应。然而，了解细胞对肌腱组织内部损伤的反应是很重要的。这是因为当细胞从其原生环境中分离出来时，许多重要的相互作用就会丧失。此外，细胞与其环境之间的相互作用对细胞行为有很强的影响。因此，本项目将开发新的技术来研究细胞在其原生组织环境中的行为。这些技术将用于了解肌腱疲劳损伤如何导致肌腱变性。这些信息将为开发肌腱疾病的新疗法提供科学基础。此外，工程专业的学生将帮助把我们的结果纳入高中生物课。我们将确定这是否会促进更多女性在工程领域的招聘和保留。本CAREER项目的研究目标是确定肌腱细胞如何在天然组织环境中感知物理刺激，并确定功能失调的细胞力学生物学在肌腱变性中的作用。主要假设是疲劳损伤改变了肌腱内细胞的物理刺激，这些改变的刺激的机械转导引发了细胞的负反应，导致肌腱变性。为了验证这一假设，研究人员将开发一种活组织外植体模型，能够同时在原位测量局部物理刺激和基因表达，并将确定驱动肌腱细胞对天然组织环境中机械负荷反应的机械转导机制。将疲劳损伤（即改变的应变和胶原组织）与细胞基因表达共定位的创新技术将识别在天然肌腱环境中引发组织变性的特定物理刺激。重要的是，外植体模型还使研究人员能够在疲劳载荷期间干扰机械转导信号通路，并研究其在诱导肌腱变性中的机制作用。除了肌腱，通过研究在2D中观察到的典型机械转导机制是否也在组织外植体中起作用，这项工作将促进对纤维软组织（如肌腱、半月板、皮肤）内细胞如何在原生组织环境中对物理刺激作出反应的广泛理解。该奖项反映了美国国家科学基金会的法定使命，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。

This Faculty Early Career Development (CAREER) grant supports research to identify how the behavior of cells within tendons is affected by tissue damage and how this leads to tendon degeneration. Previous work studied the response of tendon cells to different strains under artificial conditions. However, it is important to understand how cells response to damage inside the native tendon tissue. This is because many important interactions are lost when cells are isolated from their native environment. Also, these interactions between cells and their environment have a strong effect on cell behavior. Therefore, this project will develop novel techniques to study cell behavior in their native tissue environment. These techniques will be used to understand how tendon fatigue damage causes tendon degeneration. This information will provide the scientific foundation for developing new treatments for tendon disorders. Also, engineering students will help incorporate our results into high school biology classes. We will identify whether this improves the recruitment and retention of more women in engineering.The research goals of this CAREER project are to determine how tendon cells sense physical stimuli in the native tissue environment and to identify the role of dysfunctional cell mechanobiology in tendon degeneration. The central hypothesis is that fatigue damage alters the physical stimuli presented in situ to cells within tendon and that mechanotransduction of these altered stimuli initiates the negative cellular response leading to tendon degeneration. To test this hypothesis, the researchers will develop a live tissue explant model enabling simultaneous in situ measurement of local physical stimuli and gene expression and will identify the mechanotransduction mechanisms that drive the response of tendon cells to mechanical loading within the native tissue environment. The innovative technique of colocalizing fatigue damage (i.e., altered strains and collagen organization) with cellular gene expression will identify the specific physical stimuli that initiate tissue degeneration in the native tendon environment. Importantly, the explant model also enables the researchers to perturb mechanotransduction signaling pathways during fatigue loading and investigate their mechanistic role in inducing tendon degeneration. Beyond tendon, by investigating whether canonical mechanotransduction mechanisms observed in 2D also operate within tissue explants, this work will advance the broad understanding of how cells within fibrous soft tissues (e.g., tendon, meniscus, skin) respond to physical stimuli in the native tissue environment.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.