Collaborative Research: Uncovering Principles Underlying Rod Photoreceptor Outer Segment Renewal and Size

光感受器是在出生前后形成的神经细胞，如果它们退化就不能被替换。光感受器细胞的光感应天线是细胞的基本特征，必须不断刷新（或再生）才能最佳地捕获光。没有这个天线，感光细胞就不能感知光，感光细胞就会死亡，导致失明。这种持续的再生是通过在其基部添加新产生的蛋白质和膜以及从其尖端脱落最古老的蛋白质和膜来实现的。值得注意的是，当发生生长和脱落的动态过程时，光感受器细胞能够将其天线保持在恒定长度。这个项目的目标是发现眼睛中感光细胞用来确定其天线长度的规则。除了了解这一重要的再生过程外，该提案还将使新一代STEM学者能够学习在STEM学科中茁壮成长的关键技能。特别是，一群学生，本科生和研究生，将参与研究，并在数学/计算机建模和生命科学方面获得重要的培训和指导。该项目还包括一些活动，以增加目前和未来代表性不足的群体在STEM教育和职业中的参与。该项目旨在发现光感受器细胞用于计算和平衡其光敏天线中蛋白质和膜的生长和脱落速率的规则，以保持其细胞天线的恒定长度。利用基因操纵的斑马鱼，将发现揭示光感受器天线动态再生过程的规律。一组实验旨在刺激基地的额外增长，结果将揭示天线长度是否增加或脱落是否增加以平衡额外增长率以保持长度恒定。设计了另一组实验，其中尖端的脱落将被阻止，结果将揭示天线长度是否会由于被阻止的脱落而增加，或者底部的生长是否会减缓以平衡尖端的额外长度以保持长度恒定。最后，在实验操作后，将建立数学模型来预测光感受器天线的长度。这些模型是基于我们目前对生长和脱落的理解，其中模型输出将与天线长度的实验数据进行拟合/比较。这种模型的美妙之处在于，它可以用来帮助揭示（甚至预测，与未来的实验一起）光感受器用来保持其感觉天线恒定长度的调节机制。这一建议的结果将作为未来努力定义光感受器细胞机制的重要基础，这些机制有助于其光感天线的关键再生过程。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。

Photoreceptors are neuronal cells that form before and soon after birth, and cannot be replaced if they degenerate. The light-sensing antenna of photoreceptor cells is an essential feature of the cells and must be continuously refreshed (or regenerated) in order to optimally capture light. Without this antenna, photoreceptor cells cannot sense light, and the photoreceptor cells die, resulting in blindness. This continuous regeneration occurs by the addition of newly produced proteins and membranes at its base and by the shedding of the oldest proteins and membranes from its tip. Remarkably, the photoreceptor cell is capable of keeping its antenna at a constant length, as the dynamic processes of growth and shedding occur. The goal of this project is to discover the rules used by photoreceptor cells in the eye to determine the length of their antenna. In addition to understanding this vital regeneration process, this proposal will allow a new generation of STEM scholars to learn the skills that are vital to thrive in STEM disciplines. In particular, a cohort of students, undergraduates and graduate students, will participate in the research and gain vital training and mentoring in mathematical/computer modeling and life science. This project also incorporates activities to increase current and future participation of underrepresented groups in STEM education and careers.This project seeks to discover the rules used by photoreceptor cells to calculate and balance rates of growth and shedding of proteins and membranes in their light-sensing antenna to maintain a constant length of their cellular antennas. Rules will be discovered using genetically manipulated zebrafish that reveal the dynamic regenerative process in the photoreceptor's antenna. One set of experiments is designed to stimulate extra growth at the base, and results will reveal whether antenna length increases or whether shedding increases to balance the extra growth rate to maintain a length constant. Another set of experiments is designed in which shedding from the tip will be blocked, and results will reveal whether antenna length will increase due to blocked shedding or whether growth at the base slows to balance the extra length at the tip to maintain a length constant. Finally, mathematical models will be developed to predict the length of photoreceptor antenna following experimental manipulation. Such models are based on our current understanding of growth and shedding, where model output will be fit/compared to experimental data of antenna length. The beauty of such a model is that it can be used to help reveal (and even predict, alongside with future experiments) the regulatory mechanisms that photoreceptors use to maintain the constant length of their sensory antennas. The outcomes of this proposal will serve as an important foundation for future efforts to define the cellular machinery in photoreceptors that contribute to the critical regenerative process of their light-sensing antenna.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.