Spatial and temporal mechanisms underlying aggregate formation

该项目将解决有关细胞如何响应和管理新错误折叠和聚集的蛋白质的基本问题。蛋白质被折叠成赋予功能的特定形状；然而，通过老化或压力，蛋白质会发生错误折叠并聚集。这种由错误折叠和聚集引起的形状变化可以改变蛋白质的功能。该项目的目标是了解细胞最初如何响应和管理这些新形成的聚集体。该项目将为STEM领域的非传统群体提供培训机会，特别是将代表性不足的少数族裔和第一代学生纳入转型研究经验，从而产生更广泛的影响。此外，该项目将继续通过以探究为基础的实验室课程，为农村机构的学生提供无障碍的研究体验，其中许多是第一代学生。该项目将利用一套强大的工具，结合显微镜、遗传学和生物化学，确定在空间和时间上移动和隔离新形成的蛋白质聚集体的细胞机制。实验将确定细胞骨架网络如何促进细胞内不同类型聚集体的运输，以及聚集体如何随着时间的推移而被隔离。综上所述，该项目将在分子水平上提供细胞如何管理新形成的聚集体的机制理解，并揭示在压力或年龄存在时确保适当反应的保守途径。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 project will address fundamental questions about how cells respond to and manage newly misfolded and aggregating proteins. Proteins are folded into specific shapes that confer function; however, through aging or stress, proteins can undergo misfolding and can aggregate. This change in shape due to misfolding and aggregation can alter the function of the protein. The goal of this project is to understand how the cell initially responds and manages these newly formed aggregates. This project will have broader impacts by providing training opportunities for non-traditional groups in STEM, specifically by integrating underrepresented minorities and first-generation students in transformational research experiences. Additionally, the PI will continue to provide accessible research experiences to students at a rural institution, many of whom are first generation, through an inquiry-based laboratory course focused on protein aggregation. This project will identify the cellular mechanisms that move and sequester newly formed protein aggregates in both space and time using a powerful suite of tools that pair microscopy, genetics, and biochemistry. Experiments will determine how cytoskeletal networks contribute to the trafficking of different types of aggregates within the cell, and how aggregates are sequestered over time. Taken together, this project will provide a mechanistic understanding at the molecular level of how the cell manages newly formed aggregates and reveal conserved pathways that ensure a proper response in the presence of stress or age.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.