CAREER: Mechanical Regulation of Chromatin Motion

该奖项的首要目标是了解人类细胞核中的染色质运动如何响应外部机械刺激。染色质是DNA和蛋白质的混合物，在人类和其他生物体的细胞中形成染色体。染色质的纳米级运动可以调节细胞内DNA与调控分子的相互作用，从而影响许多基本的细胞功能，如DNA复制、DNA修复、转录，最后是基因表达。了解染色质动力学的机械调节有可能为生命系统的工程提供动力，并为疾病的治疗创造新的变革策略。该项目将特别关注核机械转导中长期存在的问题，即细胞核中染色质运动的变化是由通过细胞传递的皮牛顿力直接驱动还是由整个细胞质的扩散间接主导。初步数据清楚地表明，细胞内张力和染色质动力学都是机械敏感的，并且可能是相互联系的。本项目将设计和开发一种新的成像平台，可以同时量化机械刺激下的细胞内张力和染色质运动。此外，本项目将开发利用磁珠对活细胞进行高灵敏度、高分辨率机械扰动的实验。因此，有望实时观察细胞内张力和染色质运动的时空变化。本项目专注于染色质的动态特征，具有精密灵敏的成像系统和广泛适用的定量荧光成像分析工具。此外，该项目还将建立一个联盟，将高性能计算工具和网络基础设施集成到生物研究中。该项目将作为一种工具，提高高中学生和相关学科的本科生对计算生物学和生物物理学的教育机会和职业道路的认识。作为ACS SEED项目的一部分，每年免费向经济困难家庭的高中生提供生物影像信息夏令营。PI将在本科教学中整合计算组件。最后，在IU-MSI倡议下开发了本科生研究实习，该倡议旨在通过为项目提供短期实习机会，吸引来自少数民族服务机构的代表性不足的学生。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。

The overarching goal of this CAREER award is to understand how the chromatin motion in human cell nucleus responds to external mechanical stimuli. Chromatin is the mixture of DNA and proteins that form the chromosomes in the cells of humans and other organisms. The nanoscale movement of chromatin may modulate the interaction of DNA in the cell with regulatory molecules, which impacts many fundamental cell functions, such as DNA replication, DNA repair, transcription and, finally, gene expression. Understanding the mechanical regulation of the chromatin dynamics has the potential to power the engineering of living systems and to create new transformative strategies for the treatment of disease.This project will in particularly focus on the long-lasting question in nuclear mechanotransduction, i.e., if the change of chromatin motion in the nucleus is directly driven by the pico-Newton forces transmitted through the cell or is indirectly dominated by the diffusion throughout the cytoplasm. The preliminary data clearly concludes that both intracellular tensions and chromatin dynamics are mechanosensitive and are possibly connected. This project will design and develop a new imaging platform that can simultaneously quantify the intracellular tension and chromatin motion under mechanical stimuli. In addition, this project will develop an experiment to use a magnetic bead to mechanically disturb the live cell with high sensitivity and resolution. With this, it is expected to observe the spatiotemporal changes of the intracellular tension and chromatin motion in real-time. This project focuses on the dynamic signature of the chromatin, with an exquisitely sensitive imaging system and broadly applicable analytic tools for quantitative fluorescent imaging. In addition, this project will also develop a consortium that integrates high performance computational tools and cyberinfrastructure into biological research. This project will serve as a vehicle to increase the awareness of educational opportunities and career paths in computational biology and biophysics for high school students and undergraduates in related disciplines. An annual and free summer camp of bioimage informatics, which is part of the ACS SEED project, will be offered to high school students from economically disadvantaged families. The PI will integrate computational components into this project with the undergraduate teaching. Finally, an undergraduate research internship is developed on the IU-MSI initiative, which aims to attract underrepresented students from minority serving institutes, by providing short-term internship opportunities for the project.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.