Biophysical regulation of intercellular communication by the glycocalyx

糖萼对细胞间通讯的生物物理调节

• 批准号: 10407574
• 负责人: Matthew J Paszek
• 金额: $ 31.59万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407574
• 关键词: Accounting; Actin-Binding Protein; Actins; Biophysics; Biopolymers; Cell membrane; Cell surface; Cells; Charge; Communication; Complex; Complex Mixtures; Cytoskeleton; DNA; DNA delivery; Disease; Docking; Encapsulated; Family; Fingers; Frequencies; Gases; Generations; Genetic; Genetic Materials; Glycocalyx; Goals; Guanosine Triphosphate Phosphohydrolases; Imaging Techniques; Individual; Instruction; Investigation; Length; Ligands; Literature; Malignant Neoplasms; Membrane; Membrane Proteins; Messenger RNA; MicroRNAs; Mitochondria; Molecular; Nanotubes; Nucleic Acids; Organelles; Organism; Phenotype; Physics; Polymers; Proteins; Proteomics; Protocols documentation; Ramp; Regulation; Reporting; Research; Resolution; Role; Science; Signal Transduction; Skeleton; Small RNA; Structure; Surface; Techniques; Therapeutic; Thinness; Tissues; Tubular formation; Vesicle; base; cancer cell; cellular microvillus; density; experimental study; extracellular vesicles; flexibility; imaging approach; insight; intercellular communication; macromolecule; microvesicles; next generation; optical imaging; pressure; programs; receptor; rho; rho GTP-Binding Proteins; transcriptome sequencing

Project Summary/Abstract In a multicellular organism, every decision and action taken by a cell depends on communication with its neighbors. Lethal diseases, such as cancer, can arise when normal communication channels are disrupted. In this proposal, we investigate two specialized communication protocols that serve in the exchange of complex information packets between participating cells. In the first type, cells package proteins and genetic material into tiny, membrane-encapsulated containers, called vesicles, for delivery to recipient cells. In the second protocol, cells extend long and thin membrane tubules that form highways between participating cells for free or regulated exchange of cellular contents. Our central hypothesis is that these two important forms of intercellular communication are regulated by sugary polymers that cells assemble on their outer membrane. Like a compressed gas hovering over the cells, we propose that these sugary polymers can generate a pressure that makes it easier to bend the membrane into the spherical and tubular forms required for vesicles and intercellular highways. Thus, we anticipate that cells can ramp up communication by assembling more sugary polymers on the cell surface, or, conversely, suppress communication through a reduction of cell-surface polymers. In this proposal, our aims are to (1) determine how and what type of information is exchanged through the membrane bridges; (2) identify how the formation of the membrane bridges are controlled by the internal cellular skeleton and its regulators; and (3) determine the optimal conditions for vesicle generation and transfer of messages to participating cells. To study these possibilities, we will use sophisticated new imaging techniques capable of resolving ultrasmall cellular features, like the membrane structures that are under investigation here. We also take advantage of our ability to create DNA instruction sets that can program cells to assemble new and different polymer types on their outer membrane. A major goal is to identify the types of messages that are sent from donor to receiver cells. In addition to advanced imaging approaches, we will use powerful, “next-generation” techniques that can simultaneously identify large numbers of proteins or nucleic acids (i.e. genetic instructions), which may be part of the messages transferred. The new understanding that we seek to develop should have broad relevance in biomedicine. In particular, aggressive cancer cells often produce and attach unusual numbers of sugary polymers on their outer membrane. Thus, our studies could provide new insight into how intercellular communication goes awry in cancer, and how we might intervene therapeutically to normalize and correct the flow of information among our cells.

项目总结/摘要 在多细胞生物体中，细胞所做的每一个决定和行动都取决于与其细胞的通信。 邻居当正常的沟通渠道被破坏时，可能会出现致命的疾病，如癌症。在 在这个建议中，我们研究了两个专门的通信协议，用于交换复杂的 参与小区之间的信息分组。在第一种类型中，细胞将蛋白质和遗传物质包装成 微小的，被膜包裹的容器，称为囊泡，用于传递给受体细胞。在第二个协议中， 细胞延伸出长而薄的膜小管，在参与细胞之间形成高速公路， 细胞内容物的交换。我们的中心假设是，这两种重要的细胞间 细胞外膜上的糖聚合物调节细胞间的信息交流。像一个 当压缩气体盘旋在细胞上方时，我们认为这些含糖聚合物可以产生压力， 使其更容易弯曲成囊泡和细胞间所需的球形和管状形式 高速公路因此，我们预计细胞可以通过在细胞表面组装更多的含糖聚合物来加强交流。 细胞表面，或者相反，通过减少细胞表面聚合物来抑制通讯。在这 我们的目标是（1）确定如何以及什么类型的信息通过膜交换 （2）确定膜桥的形成如何由内部细胞骨架控制 及其调节剂;和（3）确定囊泡产生和传递信息的最佳条件， 参与细胞 为了研究这些可能性，我们将使用先进的新成像技术， 细胞特征，比如我们正在研究的膜结构。我们还利用我们的 创造DNA指令集的能力，可以编程细胞组装新的和不同的聚合物类型， 它们的外膜一个主要目标是识别从发送者发送到接收者的消息类型 细胞除了先进的成像方法，我们将使用强大的“下一代”技术， 同时识别大量的蛋白质或核酸（即遗传指令），这可能是部分 传递的信息。 我们寻求发展的新认识应该在生物医学方面具有广泛的相关性。特别是， 侵袭性癌细胞通常产生并在其外膜上附着不寻常数量的糖聚合物。 因此，我们的研究可以提供新的见解，了解细胞间通讯如何在癌症中出错，以及 我们可能会进行治疗干预，使细胞间的信息流正常化和正确化。