Biophysics of Branched Cells: Intracellular Transport, Scaling Laws and The Supply of Metabolic Demand

分支细胞的生物物理学：细胞内运输、缩放定律和代谢需求的供应

• 批准号: 2210464
• 负责人: Jonathon Howard
• 金额: $ 64.5万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2210464&HistoricalAwards=false
• 关键词: Biophysics; Branched; Cells; Intracellular; Transport

Biological cells are active materials meaning that they continuously turn over their constituent molecules as they dissipate energy obtained from metabolic processes. The physics underlying this non-equilibrium state—the material and energy fluxes together with the constraints that they impose on the organism—is only just beginning to be defined. Branched cells, such as those of the nervous and immune systems, pose especially difficult and interesting metabolic challenges. In neurons, branched dendrites collect synaptic or sensory information over a large area; yet the narrow, often bifurcated, dendritic processes must also supply materials and energy to all parts of the cell, especially to those locations undergoing growth or high activity. This project will pursue a physics-inspired approach to understand how this balance between the retrograde flow of information and the anterograde flow of nutrients impacts the morphology and function of dendrites. In this project, the group will formulate and test a supply-and-demand model that proposes that the supply of nutrients by transport processes such as molecular motor proteins match the metabolic demands of neuronal growth, activity and maintenance. The model predicts that the diameters of branched dendrites change across branch points according to specific laws that in turn depend on which cellular processes have the highest metabolic demands. These laws will be tested in living cells by combining state-of-the-art microscopy techniques with genetic and physical manipulations. It is anticipated that this project will provide insight into how the brain computes using so little energy (compared to man-made computers) and may elucidate principles that could be used in computing and engineering. The work may also improve our understanding of neurological diseases, which often arise due to the disruption of metabolic or transport processes. This work will entail training undergraduate, postgraduate and post-doctoral physics and biology studentsWhat sets the profile of diameters in branched neurons? While electrical considerations must be crucial for setting diameters, it is also necessary that axons and dendrites be of sufficient girth to provide the flux of nutrients and energy to support the growth and activity of the cell, including cytoplasm, membrane, and synapses. What are the tradeoffs between information processing and material transport? Answering these questions is important for three reasons: It will provide design rules and models that increase our basic understanding of branched cells and tissues in general; it may facilitate the segmentation of neurons for making connectomic maps and classifying cell types; and it may provide insight into why aberrant dendritic morphologies are associated with disease. Reconciliation of the different interpretations of dendrite branching may give insight into how the brain computes so energy efficiently, a holy grail for engineers and computer scientists. Because of the deep mathematical connections between electrotonic spread and diffusion, and between action potentials and active intracellular transport, optimizing information processing and material flow may not be mutually exclusive. Indeed, shared signaling and transport constraints may have permitted the development of sophisticated brains that compute efficiently. This insight, if it holds up to the scrutiny of this project, may change the way we view evolution of the brain and may have applications in computing and engineering.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.

生物细胞是活性材料，这意味着它们在消耗从代谢过程中获得的能量时不断地翻转其组成分子。这种非平衡状态的物理基础物质和能量的流动以及它们对生物体的限制才刚刚开始被定义。分支细胞，如神经和免疫系统的分支细胞，构成了特别困难和有趣的代谢挑战。在神经元中，分支树突收集大面积的突触或感觉信息;然而，狭窄的，通常是分叉的树突过程也必须为细胞的所有部分提供物质和能量，特别是那些正在生长或高度活跃的位置。该项目将采用物理启发的方法来了解信息的逆行流动和营养物质的顺行流动之间的平衡如何影响树突的形态和功能。在这个项目中，该小组将制定和测试一个供需模型，该模型提出，通过分子马达蛋白等运输过程提供的营养物质与神经元生长、活动和维持的代谢需求相匹配。该模型预测，分支树突的直径根据特定的规律在分支点上发生变化，而这些规律又取决于哪些细胞过程具有最高的代谢需求。这些定律将通过将最先进的显微镜技术与遗传和物理操作相结合，在活细胞中进行测试。预计该项目将深入了解大脑如何使用如此少的能量（与人造计算机相比）进行计算，并可能阐明可用于计算和工程的原理。这项工作还可能提高我们对神经系统疾病的理解，这些疾病通常是由于代谢或运输过程的中断而引起的。这项工作将需要培训本科生，研究生和博士后物理学和生物学学生什么设置分支神经元的直径分布？虽然电因素对于设定直径至关重要，但轴突和树突也必须具有足够的周长，以提供营养和能量的流量，以支持细胞的生长和活动，包括细胞质，膜和突触。信息处理和物质运输之间的权衡是什么？ 阐明这些问题很重要，原因有三：它将提供设计规则和模型，增加我们对分支细胞和组织的基本理解;它可能有助于神经元的分割，以制作连接图和分类细胞类型;它可能提供对异常树突状形态与疾病相关原因的深入了解。 对树突分支的不同解释的调和可能会让我们深入了解大脑如何高效地计算能量，这是工程师和计算机科学家的圣杯。由于电紧张性扩散和扩散之间，以及动作电位和主动细胞内运输之间的深刻数学联系，优化信息处理和物质流可能不是相互排斥的。事实上，共享的信号和传输约束可能已经允许开发出高效计算的复杂大脑。如果这一见解经得起这个项目的审查，它可能会改变我们看待大脑进化的方式，并可能在计算和工程中得到应用。这个奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。