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

合作研究：揭示杆状感光器外节更新和大小的基本原理

• 批准号: 1951420
• 负责人: Abigail Jensen
• 金额: $ 83.39万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1951420&HistoricalAwards=false
• 关键词: Collaborative; Research; Uncovering; Principles; Underlying

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.

光感受器是在出生前和出生后不久形成的神经元细胞，如果它们退化，则不能被替换。感光细胞的感光天线是细胞的基本特征，必须不断更新（或再生）以最佳地捕获光线。如果没有这种天线，感光细胞就不能感知光线，感光细胞就会死亡，导致失明。 这种连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，感光细胞能够保持其天线在一个恒定的长度，作为生长和脱落的动态过程发生。该项目的目标是发现眼睛中的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，该提案还将允许新一代STEM学者学习对STEM学科发展至关重要的技能。特别是，一批学生，本科生和研究生，将参加研究，并获得数学/计算机建模和生命科学的重要培训和指导。该项目还包括提高目前和未来代表性不足的群体在STEM教育和职业中的参与度的活动。该项目旨在发现感光细胞用于计算和平衡其感光天线中的蛋白质和膜的生长和脱落速率以保持其细胞天线的恒定长度的规则。规则将被发现使用基因操纵的斑马鱼，揭示感光器的天线动态再生过程。一组实验旨在刺激基部的额外生长，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的生长速率以保持长度恒定。另一组实验的设计，其中脱落的尖端将被阻止，结果将揭示天线长度是否会增加，由于阻止脱落或是否在基地的增长放缓，以平衡额外的长度在尖端，以保持长度恒定。最后，将开发数学模型来预测实验操作后的感光器天线的长度。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，以及未来的实验）光感受器用来保持其感觉天线恒定长度的调节机制。这项提案的结果将作为未来努力定义光感受器中细胞机制的重要基础，这些细胞机制有助于光感受天线的关键再生过程。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。