Cellular regulation of viscosity

细胞粘度调节

• 批准号: 10564013
• 负责人: Onn Brandman
• 金额: $ 30.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564013
• 关键词: Acute; Address; Affect; Aging; Area; Basic Science; Behavior; Biochemical Reaction; Biochemistry; Biology; Biophysical Process; Biophysics; Brain; Carbohydrates; Cell Survival; Cell physiology; Cells; Complex; Cues; Cytosol; Data; Diffusion; Disease; Disparate; Energy consumption; Environment; Feedback; Glucose; Glycogen; Health; Human; Human Resources; Human body; Hypoxia; In Vitro; Ischemic Stroke; Kinetics; Letters; Life; Link; Liver; Malignant Neoplasms; Mammalian Cell; Measures; Metabolic; Molecular; Muscle; Names; Nature; Neurodegenerative Disorders; Organism; Pathology; Pathway interactions; Phase; Polysaccharides; Production; Property; Proteins; Reaction; Regulation; Regulatory Pathway; Research; Saccharomyces cerevisiae; Saccharomycetales; Signal Pathway; Stress; Structure; System; Temperature; Testing; Up-Regulation; Viscosity; Work; Yeasts; acute stress; biological adaptation to stress; biophysical properties; cancer cell; cell growth regulation; cell type; environmental stressor; in vivo; protein folding; reaction rate; response; stress tolerance; stressor

Viscosity is fundamental to biochemical reactions and hence, life itself. Temperature affects the diffusion rate of molecules and in turn modulates the rate of reactions in non-living systems. For decades it has been assumed that cells in living organisms are subject to the same principles that connect temperature, viscosity, diffusion and reaction rates. Yet it has been a mystery how the incredibly complex diffusion-based interaction networks of a cell are robust to these fluctuations, since perturbation of reaction kinetics in even one pathway has the potential to impact multiple aspects of cellular functioning. The regulation of intracellular viscosity as a strategy to mitigate changes in diffusion due to the environment has been largely unexplored. This proposal addresses how intracellular viscosity is actively regulated, the effects of viscosity on cellular processes, and viscosity dysregulation in disease. We recently discovered that cytosolic diffusion rates and viscosity-controlled reaction rates are held invariant across at least 20° C of steady state temperatures in Saccharomyces cerevisiae. We found that cellular viscosity temporarily increases in response to acute stress. We named this phenomenon “viscoadaptation”. Viscoadaptation is both a homeostatic mechanism for maintaining constant viscosity despite fluctuations in temperature as well as an acute response to a variety of environmental stressors. Viscoadaptation acts via production of the viscous carbohydrate glycogen that is linked to human health and disease, and we hypothesize that low energy levels trigger viscoadaptation. The discovery of viscoadaptation marks a major advance in our understanding of how cells regulate their biophysical properties. Yet many mysteries remain, including 1) how viscodaptation affects the biophysical properties of cells, 2) what signaling pathways regulate viscoadaptation. We propose to (aim 1) study the effect of glycogen on protein mobility and structure (aim 2) investigate how the pathways regulating viscosity in yeast and human cells. The proposed studies will examine regulation of a fundamental yet largely unexplored biophysical feature of cells, viscosity. This will elucidate the long overlooked contribution of viscosity to critical cellular processes and the mechanisms by which this fundamental property is actively regulated in cells. In doing so, this work has the potential to reframe disease conditions from the perspective of viscosity dysregulation and usher in a new conceptual framework of "viscosity-related" pathologies.

粘度是生化反应的基础，因此温度本身也会影响生命。 几十年来，它一直在影响分子的扩散速率，进而调节非生命系统中的反应速率。 假设活体细胞遵循与温度相关的相同原理， 然而，基于扩散的极其复杂的过程如何一直是个谜。 细胞的相互作用网络对这些波动具有鲁棒性，因为即使在一个细胞中，反应动力学的扰动也是如此。 途径有可能影响细胞功能的多个方面。 粘度作为减轻环境引起的扩散变化的策略已在很大程度上得到了应用 该提案解决了细胞内粘度如何主动调节的问题。 细胞过程中的粘度和疾病中的粘度失调。 我们最近发现细胞质扩散速率和粘度控制反应速率保持不变 我们发现酿酒酵母在至少 20°C 的稳态温度下保持不变。 细胞粘度因急性应激而暂时增加，我们将这种现象命名为“细胞粘度”。 “粘性适应”是一种维持恒定粘性的稳态机制。 温度波动以及对各种环境压力的急性反应。 粘性适应通过产生粘性碳水化合物糖原来发挥作用，粘性碳水化合物糖原与人类健康和 疾病，我们追求低能量水平会引发粘性适应。 粘性适应的发现标志着我们对细胞如何调节的理解取得了重大进展 然而，它们的生物物理特性仍然存在许多谜团，包括 1) 粘性适应如何影响生物物理。 细胞的特性，2）什么信号通路调节粘性适应。我们建议（目标 1）研究 糖原对蛋白质流动性和结构的影响（目标 2）研究途径如何调节 酵母和人体细胞的粘度。 拟议的研究将检查基本但很大程度上尚未探索的生物物理的调节 细胞的特征，粘度，这将阐明长期被忽视的粘度对关键细胞的贡献。 细胞中这一基本特性受到积极调节的过程和机制。 这项工作有可能从粘度失调的角度重新定义疾病状况 引入“粘度相关”病理学的新概念框架。