Understanding Regulators of Collagen Crosslinking Enzymes for Tendon Formation

了解肌腱形成中胶原交联酶的调节剂

• 批准号: 2145004
• 负责人: Nathan Schiele
• 金额: $ 40.23万
• 依托单位: Regents of the University of Idaho
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2145004&HistoricalAwards=false
• 关键词: Understanding; Regulators; Collagen; Crosslinking; Enzymes

Tendons act as a mechanical connection from muscle to bone. Understanding how tendons develop mechanical function is important because tendon injuries are common, treatment options are limited, and damaged tendons rarely regain their full strength. Collagen is a major contributor to tendon strength. However, much is unknown about the conditions that influence collagen formation during normal tendon development. For example, several types of enzymes crosslink and stabilize collagen in tendons, but how cells coordinate the production of these collagen crosslinking enzymes during tendon development is unknown. This project addresses this knowledge gap by exploring the signals that control enzyme production by cells. This research will generate new knowledge on how collagen crosslinking is regulated. Findings from this research will contribute to a greater understanding of the mechanisms of tendon formation and may lead to advanced therapies to treat the altered mechanical function and disability found with tendon injuries. Integral to the project are activities to improve retention in STEM and the diversity of graduates in engineering. The project creates hands-on research experiences and the writing exercises for students enrolled in a multidisciplinary engineering course. It also funds undergraduates to conduct faculty-mentored research, develop and submit NSF graduate research fellowship applications, and present their research at scientific conferences. Finally, the project includes K-12 outreach activities and laboratory tours.The scientific goal of this research is to define the mechanisms that control collagen crosslinking enzyme production by cells. Adult stem cells and tendon cells isolated from developing rat tendons associated with high forces, the Achilles tendon, and low forces, the tail tendon, will be evaluated in culture as model systems to determine if these cell populations have unique control mechanisms. To test mechanically responsive pathways that regulate collagen crosslinking enzyme production, cells will be exposed to a range of mechanical stimuli using a bioreactor and treated with targeted cell signaling pathway inhibitors. The role of biological signaling in enzyme production will be evaluated using different biochemical growth factors that are known to impact tendon growth and injury, while conducting cell signaling pathway inhibition and analysis. Research outcomes will advance knowledge of the mechanisms that regulate collagen crosslinking enzyme production by tendon and stem cells. This project is jointly funded by Biomechanics & Mechanobiology (BMMB) Program and the Established Program to Stimulate Competitive Research (EPSCoR).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.

肌腱作为肌肉和骨骼之间的机械连接。了解肌腱如何发展机械功能是很重要的，因为肌腱损伤是常见的，治疗方案是有限的，受损的肌腱很少恢复其全部力量。胶原蛋白是肌腱强度的主要贡献者。然而，在正常肌腱发育过程中，影响胶原蛋白形成的条件仍不清楚。例如，几种类型的酶交联并稳定肌腱中的胶原蛋白，但细胞如何在肌腱发育期间协调这些胶原交联酶的产生尚不清楚。该项目通过探索控制细胞产生酶的信号来解决这一知识缺口。这项研究将产生关于胶原蛋白交联如何调节的新知识。这项研究的结果将有助于更好地了解肌腱形成的机制，并可能导致先进的治疗方法来治疗肌腱损伤所发现的机械功能改变和残疾。该项目的组成部分是提高STEM保留率和工程毕业生多样性的活动。该项目为参加多学科工程课程的学生创造了实践研究经验和写作练习。它还资助本科生进行教师指导的研究，开发和提交NSF研究生研究奖学金申请，并在科学会议上展示他们的研究。最后，该项目包括K-12外展活动和实验室参观图尔斯。本研究的科学目标是确定控制细胞产生胶原交联酶的机制。成人干细胞和肌腱细胞分离自发育中的大鼠肌腱与高力，跟腱，和低力，尾腱，将在培养中作为模型系统进行评价，以确定这些细胞群是否具有独特的控制机制。为了测试调节胶原交联酶产生的机械响应途径，将使用生物反应器将细胞暴露于一系列机械刺激，并用靶向细胞信号传导途径抑制剂处理。生物信号传导在酶产生中的作用将使用已知影响肌腱生长和损伤的不同生化生长因子进行评估，同时进行细胞信号传导途径抑制和分析。研究结果将促进肌腱和干细胞调节胶原交联酶产生的机制的知识。该项目由生物力学机械生物学（BMMB）计划和刺激竞争研究的既定计划（EPSCoR）共同资助。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。