CAREER: Mechanical Regulation of Chromatin Motion

这一职业奖的首要目标是了解人类细胞核中的染色质运动如何对外部机械刺激做出反应。染色质是DNA和蛋白质的混合物，它们构成了人类和其他生物细胞中的染色体。染色质的纳米级运动可能会调节细胞内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、转录以及最终的基因表达。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性策略。本项目将特别关注核机械转导中的长期问题，即细胞核内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，还是间接由整个细胞质的扩散主导。初步数据清楚地得出结论，细胞内张力和染色质动力学都是机械敏感的，可能是相关的。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细胞内的张力和染色质的运动。此外，该项目还将开发一项实验，利用磁珠以高灵敏度和高分辨率对活细胞进行机械干扰。据此，有望实时观察细胞内张力和染色质运动的时空变化。该项目重点研究染色质的动态特征，具有精致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，该项目还将发展一个将高性能计算工具和网络基础设施整合到生物研究中的联合体。该项目将作为一种工具，提高相关学科的高中生和本科生对计算生物学和生物物理学方面的教育机会和职业道路的认识。作为ACS SEED项目的一部分，将为来自经济困难家庭的高中生提供一年一度的免费生物图像信息学夏令营。PI将在本科教学中将计算组件整合到这个项目中。最后，根据IU-MSI的倡议，开发了一个本科生研究实习，旨在通过为该项目提供短期实习机会，吸引少数族裔服务机构中代表性不足的学生。该奖项反映了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 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.