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: 10178052
• 负责人: Matthew J Paszek
• 金额: $ 31.62万
• 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/10178052
• 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.

项目摘要/摘要 在多细胞生物中，一个细胞所采取的每个决定和行动都取决于与其的交流 邻居。当正常沟通渠道破坏时，可能会出现致命疾病，例如癌症。在 这项建议，我们调查了两个专门的交流协议，这些协议用于复杂的交换 参与细胞之间的信息数据包。在第一种类型中，细胞将蛋白质和遗传物质包装到 微小的，膜封装的容器，称为蔬菜，用于输送到受体细胞。在第二个协议中， 细胞延伸长而薄的膜管，它们在参与细胞之间自由或调节形成高速公路 交换细胞含量。我们的中心假设是这两种重要形式的细胞间形式 通信受细胞在其外膜上组装的含糖聚合物的调节。像 压缩气体徘徊在细胞上，我们建议这些含糖聚合物可以产生一个压力， 使将膜弯曲成蔬菜和细胞间所需的球形和管状形式变得更容易 高速公路。这是，我们预计细胞可以通过在 细胞表面，或相反，通过还原细胞表面聚合物来抑制通信。在这个 提案，我们的目的是（1）确定通过膜交换的方式和哪种信息 桥梁； （2）确定如何通过内部细胞骨架控制膜桥的形成 及其监管机构； （3）确定信息的最佳条件和消息传输到 参与细胞。 为了研究这些可能性，我们将使用能够解决Ultrasmall的复杂新成像技术 细胞特征，例如这里正在研究的膜结构。我们还利用我们的 能够创建DNA指令集，可以编程细胞以组装新的和不同的聚合物类型 他们的外膜。一个主要目标是确定从捐助者发送到接收者的消息类型 细胞。除了高级成像方法外，我们还将使用强大的“下一代”技术 类似地识别大量蛋白质或核酸（即遗传说明），这可能是部分 传输的消息。 我们寻求发展的新理解应该在生物医学上具有广泛的相关性。尤其， 侵略性癌细胞通常会在其外膜上产生异常数量的含糖聚合物。 这就是我们的研究可以提供有关细胞间沟通如何在癌症中出现错误的新见解，以及如何 我们可能会热干预以正常并纠正细胞之间的信息流。