BRITE Pivot: Identification of the Biophysical Mechanisms Regulating Nuclear-Cytosolic Transport Capacity

这个促进工程中变革性和公平性进步的研究思路(BRITE)轴心研究项目的总体目标是全面了解大分子进出细胞核的生物物理规律。细胞核是细胞中最大的结构，DNA周围有两层膜。这种双层膜有数千个小孔，称为核孔复合体(NPC)。核祖细胞是分子(包括蛋白质和信使核糖核酸)进出细胞核的方式。这种通过npc的分子运动是如此重要，以至于哺乳动物(人类)和单细胞生物体都有它。鼻咽癌转运问题出现在许多疾病中，包括癌症、病毒感染、心血管疾病和衰老。因为几乎每个细胞都有一个核，所以测量通过核细胞的分子的新方法将对细胞生物学、生物物理学和机械生物学的研究有用。该项目的教育目标是通过在教育和推广经验中使用这些新的研究成果，向本科生介绍不断增长的核机械生物学领域。对单个核孔复合体的大分子结构进行了详细的表征，包括许多核孔蛋白的定位和动力学。然而，在空间和时间层面上，鼻咽癌核运输的动态和调控尚未得到仔细研究，部分原因是检测这些过程的工具有限。在这个项目中，将开发和应用基于生物传感器的方法来更好地了解NPC核运输，以了解调控NPC运输的生化和生物力学因素。这些研究的结果将为深入了解有关NPC运输调控的尚未回答的基本问题提供实质性的见解：1)NPC运输活动是否存在空间差异？2)个别NPC是否专门从事进口和出口？3)核祖细胞的机械负荷是否改变了核-胞质运输？这项变革性的研究将对鼻咽癌核-胞质转运的生物物理调节提供新的理解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The overall goal of this Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Pivot research project is to develop a comprehensive understanding of the biophysical regulation of the movement of large molecules in and out of the cell nucleus. The nucleus is the largest structure in a cell and has two membranes surrounding the DNA. The double membrane has thousands of small pores called nuclear pore complexes (NPCs). The NPCs are how molecules (including proteins and mRNA) move into and out of the nucleus. This movement of molecules through NPCs is so important that mammals (humans) and single-cell organisms all have it. Problems with NPC transport occurs in many diseases, including cancer, infection by viruses, cardiovascular disease, and aging. Because nearly every cell has a nucleus, the new methods for measuring the molecules moving through the NPCs will be useful for research in cell biology, biophysics, and mechanobiology. The educational goal of this project is to introduce undergraduate students to the growing field of nucleus mechanobiology by using these new research findings in educational and outreach experiences.The macromolecular structure of individual nuclear pore complexes (NPCs) has been characterized in great detail, including the localization and dynamics of many nucleoporin proteins. However, the dynamics and regulation of NPC nuclear transport, at a spatial and temporal level, have yet to be carefully studied, in part due to a limitation in tools for detection of these processes. In this project biosensor-based approaches will be developed and applied to better understand NPC nuclear transport in order to understand of the biochemical and biomechanical factors that regulate NPC transport. Results from these studies will provide substantial insight into yet-unanswered fundamental questions concerning NPC regulation of transport: 1) are there are spatial differences in NPC transport activity? 2) are individual NPCs specialized for import versus export? and 3) does mechanical loading of NPCs alter nuclear-cytosolic transport? This transformative research will provide a new understanding of the biophysical regulation of NPC nuclear-cytosolic transport.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.