Cellular dynamics during zebrafish hair cell death, differentiation, and regeneration

项目总结 内耳内的感觉毛细胞容易受到环境毒素的破坏和死亡， 包括暴露在巨大的噪音和某些类型的药物中。因为成年哺乳动物几乎没有能力 再生毛细胞，毛细胞的丧失会导致人类永久性的听力和平衡障碍。相比之下， 非哺乳类脊椎动物，如鱼、青蛙和鸟类，可以在一生中旺盛地再生毛细胞， 使成年人在受损后能够恢复功能。在这些动物中，附近的支持细胞充当毛细胞。 祖先。在支持细胞的形状、结构和运动性方面观察到不同 再生和非再生生物体，但这些因素是否直接调节再生 产能尚不清楚。该项目试图使用斑马鱼侧线神经肥大的活体成像来表征 支持毛细胞死亡、分化和再生过程中的细胞形态和动态。目标之一就是 项目是使用定量细胞形状分析来确定支持细胞形状和 命运。最终，这可能使使用细胞形态来预测哪些支持细胞将充当毛发成为可能 细胞祖细胞。该项目的另一个重点是了解肌球蛋白收缩如何调节毛细胞 挤出、分化和再生。肌动蛋白细胞骨架是细胞形态的主要决定因素， 动力学和支持细胞的F-肌动蛋白结构在成年哺乳动物和非哺乳动物中是不同的。 从这些研究中获得的信息可能有助于研究人员设计刺激毛细胞的疗法 成年哺乳动物的再生。重要的是要考虑再生疗法将如何影响 内耳细胞的形状和结构，因为内耳器官的功能高度依赖于 正确的单元格方向和组织。该项目将在David Raible博士在该大学的实验室进行 华盛顿拥有丰富的培训环境，拥有研究斑马鱼毛细胞的丰富专业知识和资源。 这些研究将与定量细胞生物学和生物物理学的专家合作完成，他们将 为首席调查员提供其他资源和指导。该项目包括一项培训计划 这将使首席调查员获得成像、建模和编程经验，从而成为 独立研究科学家，应用跨学科方法研究细胞和发育生物学。

PROJECT SUMMARY Sensory hair cells within the inner ear are susceptible to damage and death from environmental toxins, including exposure to loud noise and some types of drugs. Because adult mammals have little to no capacity to regenerate hair cells, hair cell loss causes permanent hearing and balance impairments in humans. In contrast, nonmammalian vertebrates like fish, frogs, and birds can robustly regenerate hair cells throughout life, enabling functional recovery after damage in adults. In these animals, nearby support cells act as hair cell progenitors. Differences in support cell shape, structure, and motility have been observed between regenerating and non-regenerating organisms, but whether these factors directly regulate regenerative capacity is unclear. This project seeks to use live imaging of zebrafish lateral line neuromasts to characterize support cell shape and dynamics during hair cell death, differentiation, and regeneration. One aim of the project is to use quantitative cell shape analysis to determine the relationship between support cell shape and fate. Ultimately, this may make it possible to use cell morphology to predict which support cells will act as hair cell progenitors. Another focus of the project is to understand how actomyosin contractility regulates hair cell extrusion, differentiation, and regeneration. The actin cytoskeleton is a major determinant of cell shape and dynamics, and support cell F-actin structure is known to differ in adult mammals compared to non-mammals. The information gained from these studies may help investigators design therapies to stimulate hair cell regeneration in adult mammals. It will be important to consider how regenerative therapies will impact the shape and structure of cells in the inner ear because the function of inner ear organs is highly dependent on correct cell orientation and organization. This project will take place in Dr. David Raible's lab at the University of Washington, a rich training environment with abundant expertise and resources to study zebrafish hair cells. These studies will be done in collaboration with experts in quantitative cell biology and biophysics, who will provide additional resources and guidance for the principal investigator. The project includes a training plan that will see the principal investigator gain imaging, modeling, and programming experience to become an independent research scientist applying interdisciplinary approaches to cell and developmental biology.