RII Track-4: Mechanical Regulation of Intra-Nuclear Mechanics and Gene Transcription

RII Track-4：核内力学和基因转录的机械调节

• 批准号: 1929188
• 负责人: Gunes Uzer
• 金额: $ 21.36万
• 依托单位: Boise State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929188&HistoricalAwards=false
• 关键词: RII; Track; Mechanical; Regulation; Intra

All living organisms, from animals to single cells, adapt to environmental challenges to survive and function. In humans, for example, mechanical signals generated by exercise is universally recognized to combat obesity, maintain a healthy musculoskeletal system and improve quality of life. However, at the cellular level, how these mechanical signals accomplish their function remains as a critical knowledge gap that precludes us from understanding its underlying principles. The aim of this project, through using state of the art technologies, is to address this knowledge gap and promote scientific progress. Understanding how environmental forces (wind, solar, electrical and mechanical) regulate cell function is a first critical step in reverse engineering the cell functions in order to generate next generation of solutions for broad range of problems from health care to energy sustainability. To increase the positive long-term impact on environmental and other goals of the nation, tools generated will be disseminated across many platforms: undergraduate students will be trained through yearly internships, concepts will be transferred via graduate classes and new collaborations will be formed between researchers during summer workshops. The proposed research program will be an excellent platform to fascinate next generation students and researchers.Cellular adaptation to the local mechanical environment requires orchestration from the moment of reception to distal gene transcription. Central to this function, the nucleus responds to external stimuli or its molecular transducers by regulating intra-nuclear organization that ultimately determines gene expression to control cell function and fate. While knowledge about individual processes including, mechanoreception, genomic organization and transcription are exceedingly detailed, efforts to unify this information into a set of deterministic rules is lacking. The long-term goal of this research is to generate predictive models of how the chromatin nano-environment adapts to the cellular macro-environment to control gene expression. As a first critical step in answering this overarching question, this project will focus on currently unknown spatial relationships between local nuclear stiffening and mRNA transcription in living cells. By uniquely combining deformation microscopy method with the tracking of mRNA transcription at a single gene locus, this project aims to correlate full-field strain in the live nucleus with the real-time mRNA transcription in mechanically challenged stem cells. Correlations between subnuclear mechanics and mRNA transcription will advance the scientific knowledge on how external mechanical force regulates cell function. The PI aims to receive training to transfer the deformation microscopy technique into Boise State University and combine it with live mRNA tracking and adipogenic MSC differentiation model.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.

所有生物体，从动物到单细胞，都适应环境挑战以生存和发挥作用。例如，在人类中，运动产生的机械信号被普遍认为可以对抗肥胖，保持健康的肌肉骨骼系统并提高生活质量。然而，在细胞水平上，这些机械信号如何完成其功能仍然是一个关键的知识缺口，使我们无法理解其基本原理。该项目的目的是通过使用最先进的技术，解决这一知识差距，促进科学进步。 了解环境力量（风能，太阳能，电力和机械）如何调节细胞功能是逆向工程细胞功能的第一个关键步骤，以便为从医疗保健到能源可持续性的广泛问题产生下一代解决方案。为了增加对国家环境和其他目标的长期积极影响，所产生的工具将在许多平台上传播：本科生将通过年度实习进行培训，概念将通过研究生课程进行转移，研究人员之间将在夏季研讨会期间形成新的合作。拟议的研究计划将成为吸引下一代学生和研究人员的绝佳平台。细胞对局部机械环境的适应需要从接收到远端基因转录的时刻进行编排。 细胞核对外界刺激或其分子转换器的反应是通过调节核内组织来实现的，核内组织最终决定基因表达，从而控制细胞的功能和命运。 虽然关于包括机械感受、基因组组织和转录在内的个体过程的知识非常详细，但缺乏将这些信息统一为一组确定性规则的努力。这项研究的长期目标是生成染色质纳米环境如何适应细胞宏观环境以控制基因表达的预测模型。作为回答这个首要问题的第一个关键步骤，该项目将重点关注活细胞中局部核硬化和mRNA转录之间目前未知的空间关系。通过将变形显微镜方法与单个基因位点的mRNA转录跟踪相结合，该项目旨在将活细胞核中的全场应变与机械挑战干细胞中的实时mRNA转录相关联。亚核力学和mRNA转录之间的相关性将促进外部机械力如何调节细胞功能的科学知识。PI旨在接受培训，将变形显微镜技术转移到博伊西州立大学，并将其与活mRNA跟踪和脂肪形成MSC分化模型相结合。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。

项目成果

Lamin A/C Is Dispensable to Mechanical Repression of Adipogenesis.

• DOI: 10.3390/ijms22126580
• 发表时间: 2021-06-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Goelzer M;Dudakovic A;Olcum M;Sen B;Ozcivici E;Rubin J;van Wijnen AJ;Uzer G
• 通讯作者: Uzer G

Low Intensity Vibrations Augment Mesenchymal Stem Cell Proliferation and Differentiation Capacity during in vitro Expansion

• DOI: 10.1038/s41598-020-66055-0
• 发表时间: 2020-06-10
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Bas, Guniz;Loisate, Stacie;Uzer, Gunes
• 通讯作者: Uzer, Gunes