Towards a molecular mechanism for mechanosensitive gene regulation

寻找机械敏感基因调控的分子机制

• 批准号: 8317223
• 负责人: Benjamin L Ricca
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317223
• 关键词: Adhesives; Affect; Apoptosis; Atomic Force Microscopy; Behavior; Biochemistry; Biological Assay; Biological Process; Biophysics; Cell Count; Cell Culture Techniques; Cell physiology; Cells; Chromosome Mapping; Complex; Cytoskeleton; DNA biosynthesis; Development; Drug Delivery Systems; Environment; Event; Feedback; Fibroblasts; Fluorescence Microscopy; Focal Adhesions; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Health; Hour; Image; Individual; Knowledge; Life; Link; Measures; Mechanics; Medical Technology; Mesenchymal Stem Cells; Messenger RNA; Methods; Molecular; Monitor; Nature; Neoplasm Metastasis; Output; Pattern; Pharmacotherapy; Physiologic pulse; Positioning Attribute; Process; Signal Transduction; Staging; Stimulus; Structure; Surface; Techniques; Testing; Time; Tissue Engineering; Tissues; Transcript; Transcriptional Regulation; United States National Institutes of Health; Work; cancer therapy; cantilever; design; experience; improved; insight; light microscopy; regenerative; regenerative therapy; research study; response; stem cell differentiation; therapeutic target; transcription factor; tumor; tumor progression

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.

描述(由申请人提供)：细胞的机械微环境会影响其行为，从其黏附和细胞骨架结构到其表达的基因，并已被证明影响复杂的生物学过程，如干细胞分化和肿瘤进展。然而，细胞如何测量和解释其微环境中的机械信息，特别是瞬时机械信号，如在发育和损伤过程中经历的信号，目前尚不清楚。这项拟议的工作将通过使用力显微镜直接成像活细胞中随着机械微环境的改变而积累的mRNA转录本和转录因子的定位来探索这些问题。通过这种方式，我们将能够破译机械刺激的阈值，包括硬度变化或力变化，以及机械输入的模式，包括连续的、振荡的和脉冲的刺激，它们可以引发遗传反应，并改变机械输入的模式，以确定细胞如何将瞬时的短时间尺度的机械输入整合到持续的长时间尺度遗传反应中，从而将我们推向机械敏感基因调节的详细机制。 公共卫生相关性：肿瘤进展和干细胞分化是细胞过程，受到细胞所处的机械微环境的影响，尽管细胞如何在其微环境中感知和解释机械信息并不是很清楚。这项拟议的工作将促进我们对这一感知过程的了解，确定可以作为药物治疗靶点的关键部分，并告知如何设计用于再生治疗的工程组织。