ERI: The Role of a Novel Mechanosensitive Channel Modulator in Inflammation

该工程研究启动（ERI）奖将支持细胞如何检测机械负荷（机械转导）的研究。机械转导将机械负荷转化为生物反应。机械触发的细胞表面开口（机械敏感通道）是最著名的细胞力感应系统。它们对触觉和听觉很重要，对许多人类疾病都有影响。该领域的一个研究挑战是发现能够选择性地触发机械敏感离子通道的分子。已知一些分子可以触发这些通道，但它们如何起作用尚不清楚。了解这些人造分子的功能可以在很多方面提供帮助，包括接受它们作为治疗人类疾病的药物。该奖项支持的研究目标是发现一种新的机械敏感通道调制器的作用机制。这项研究的结果可以用来了解与通道相关的疾病，为社会带来好处。进一步的好处将通过多学科的研究活动来实现，这些活动将使多个未被充分代表的群体参与研究。压电（Piezo1和Piezo2）机械敏感通道是非选择性阳离子机械敏感通道，在听觉、触觉和炎症等多种生理过程中发挥重要作用。这个项目的目标是研究新的Piezo1调节剂在炎症中的作用。这一目标将通过以下方式实现：i)识别和表征一种新型Piezo1激活剂，这将为未来的机械敏感通道研究提供一个基本平台；Ii)电容钳技术的发展对研究机械敏感通道的生物力学特性至关重要，为研究离子通道提供了电生理学平台；Iii)建立用于炎症研究的星形胶质细胞培养模型；iv)提供炎症的潜在机制。该项目的主要成果将是发现一种新的治疗策略，通过靶向Piezo1来治疗炎症，这将促进神经科学、发育生物学和免疫学的研究和教育。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 Engineering Research Initiation (ERI) award will support research on how cells detect mechanical loading (mechanotransduction). Mechanotransduction converts mechanical load into a biological response. Mechanically triggered openings in the cell surface (mechanosensitive channels) are the best-known cellular force-sensing systems. They are important for the senses of touch and hearing and have effects in many human diseases. A research challenge for the field is discovering molecules that can selectively trigger a mechanosensitive ion channel. Some molecules are known for triggering these channels but how they function in not known. Knowing how these artificial molecules function could help in many ways, including acceptance of them as a drug for treating diseases in people. The research supported by this award has the goal of discovering the mechanism of action for a new mechanosensitive channel modulator. Results from this research could be used to understand channel-associated diseases, producing benefits for society. Further benefits will be achieved through the multi-disciplinary research activities that will engage multiple underrepresented groups in research. Piezo (Piezo1 and Piezo2) mechanosensitive channels are non-selective cation mechanosensitive channels, playing important roles in diverse physiological processes, including hearing, touching, and inflammation. The goal of this project is to investigate the roles of new Piezo1 modulator on inflammation. This aim will be achieved by: i) identifying and characterize a novel Piezo1 activator, which will generate a fundamental platform for future mechanosensitive channel studies; ii) development of a capacitance clamp technique that is critical to study the biomechanical properties of mechanosensitive channels and provides an electrophysiological platform for studying ion channels; iii) development of a cultured astrocyte cell model for inflammation studies; and iv) providing the underlying mechanism of inflammation. The major outcome of this project will be the discovery of a novel therapeutic strategy for treating inflammation by targeting Piezo1 that will promote research and education in neuroscience, developmental biology, and immunology.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.