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: 10033749
• 负责人: Matthew J Paszek
• 金额: $ 31.64万
• 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/10033749
• 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.

项目概要/摘要 在多细胞生物体中，细胞做出的每一个决定和行动都取决于与其细胞的沟通。 当正常的沟通渠道被破坏时，就会出现致命的疾病，例如癌症。 在这个提案中，我们研究了两种专门的通信协议，它们用于交换复杂的数据 在第一种类型中，细胞将蛋白质和遗传物质包装成信息包。 微小的膜封装容器，称为囊泡，用于递送至受体细胞。 细胞延伸出长而薄的膜管，在参与细胞之间形成自由或受调节的高速公路 我们的中心假设是细胞间的这两种重要形式。 通讯由细胞在其外膜上组装的糖聚合物调节。 压缩气体盘旋在细胞上，我们认为这些糖聚合物可以产生压力 使膜更容易弯曲成囊泡和细胞间质所需的球形和管状形式 因此，我们预计细胞可以通过在高速公路上组装更多的糖聚合物来加强通讯。 细胞表面，或者相反，通过减少细胞表面聚合物来抑制通讯。 建议，我们的目标是（1）确定通过膜交换信息的方式和类型 桥；（2）确定内部细胞骨架如何控制膜桥的形成 及其调节者；（3）确定囊泡生成和传递信息的最佳条件 参与细胞。 为了研究这些可能性，我们将使用能够解析超小物体的复杂的新成像技术 细胞特征，例如正在研究的膜结构，我们也利用了我们的优势。 能够创建 DNA 指令集，对细胞进行编程以组装新的和不同的聚合物类型 它们的外膜的一个主要目标是识别从捐赠者发送到接收者的消息类型。 除了先进的成像方法之外，我们还将使用强大的“下一代”技术。 同时识别大量蛋白质或核酸（即遗传指令），这可能是 传输的消息数。 我们寻求发展的新认识应该在生物医学领域具有广泛的相关性。 侵袭性癌细胞通常会在其外膜上产生并附着异常数量的糖聚合物。 因此，我们的研究可以为细胞间通讯如何在癌症中出错以及如何发生问题提供新的见解。 我们可能会进行治疗干预，以使细胞之间的信息流正常化并纠正。