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

项目摘要 内耳内的感觉毛细胞容易受到环境毒素的损害和死亡， 包括暴露在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 毛细胞再生，毛细胞的损失会导致永久性的听力和人类的平衡障碍。与此相反， 非哺乳类脊椎动物，如鱼、青蛙和鸟类，一生中都能强健地再生毛细胞， 使成年人在损伤后能够恢复功能。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， 再生和非再生生物，但这些因素是否直接调节再生 能力不清楚。该项目旨在使用斑马鱼侧线神经瘤的实时成像来表征 在毛细胞死亡、分化和再生期间支持细胞形状和动力学。的一个目的 项目是使用定量细胞形状分析，以确定支持细胞形状和 命运最终，这可能使使用细胞形态学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动球蛋白收缩性如何调节毛细胞 挤压、分化和再生。肌动蛋白细胞骨架是细胞形状的主要决定因素， 动力学和支持细胞F-肌动蛋白结构已知与非哺乳动物相比在成年哺乳动物中不同。 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 内耳中细胞的形状和结构，因为内耳器官的功能高度依赖于 正确的细胞方向和组织。该项目将在该大学大卫·雷布尔博士的实验室进行 华盛顿，一个丰富的培训环境与丰富的专业知识和资源，研究斑马鱼毛细胞。 这些研究将与定量细胞生物学和生物物理学专家合作完成，他们将 为主要研究者提供额外的资源和指导。该项目包括一个培训计划 这将使首席研究员获得成像、建模和编程经验， 独立研究科学家，运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.