Towards a molecular mechanism for mechanosensitive gene regulation

描述（由申请人提供）：细胞的机械微环境影响其行为，从其粘附和细胞骨架结构到其表达的基因，并且已显示影响复杂的生物学过程，如干细胞分化和肿瘤进展。然而，细胞在其微环境中测量和解释机械信息的方式，特别是瞬态机械信号，例如在发育和创伤期间经历的那些，尚不清楚。拟议的工作将探索这些问题，直接成像的mRNA转录本和转录因子的积累在活细胞中的机械微环境的改变，使用力显微镜。通过这种方式，我们将能够破译机械刺激的阈值，包括刚度变化或力的变化，以及机械输入的模式，包括连续，振荡和脉冲刺激，可以引起遗传反应，并改变机械输入的模式，以确定细胞如何将短暂的短时间尺度机械输入整合到持续的长时间尺度遗传反应中，使我们更深入地了解机械敏感基因调控的详细机制。 公共卫生相关性：肿瘤进展和干细胞分化是受细胞所处的机械微环境影响的细胞过程，尽管细胞如何感知和解释其微环境中的机械信息尚不清楚。拟议的工作将推进我们对这种传感过程的了解，确定可以作为药物治疗靶点的关键部分，并为如何设计再生治疗的工程组织提供信息。

DESCRIPTION (provided by applicant): A cell's mechanical microenvironment an influence its behavior, from its adhesive and cytoskeletal structure to the genes it expresses, and has been shown to affect complex biological processes such as stem cell differentiation and tumor progression. However, the manner in which a cell measures and interprets mechanical information in its microenvironment, particularly transient mechanical signals such as those experienced during development and wounding, is unclear. The proposed work will explore these questions by directly imaging the accumulation of mRNA transcripts and transcription factor localization in live cells as the mechanical microenvironment is altered using force microscopy. In this way, we will be able to decipher the thresholds of mechanical stimuli, include stiffness changes or force changes, and the patterns of mechanical inputs, including continuous, oscillatory, and pulsed stimuli, that can elicit a genetic response, and vary the patterns of mechanical inputs to determine how a cell integrates transient short-timescale mechanical inputs into sustained long-timescale genetic responses, moving us toward a detailed mechanism for mechanosensitive gene regulation. PUBLIC HEALTH RELEVANCE: Tumor progression and stem cell differentiation are cellular processes that are affected by the mechanical microenvironment a cell finds itself in, though how a cell senses and interprets mechanical information in its microenvironment is not well understood. The proposed work will advance our knowledge of this sensing process, identifying key parts that could serve as targets for drug therapies and informing how to design engineered tissues for regenerative therapies.