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.

项目摘要/摘要 在多细胞有机体中，细胞所做的每一项决定和采取的每一项行动都依赖于与其 邻里。当正常的沟通渠道中断时，可能会出现致命的疾病，如癌症。在……里面 在这个方案中，我们研究了两个专门的通信协议，它们服务于复杂的交换 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 微小的薄膜包裹的容器，称为囊泡，用于运送到受体细胞。在第二协议中， 细胞在参与的细胞之间自由或受调节地延伸形成高速公路的长而薄的膜管 交换蜂窝内容。我们的中心假设是，细胞间的这两种重要形式 细胞在外膜上组装的含糖聚合物调节着细胞间的通讯。就像一个 压缩气体在细胞上方盘旋，我们认为这些含糖聚合物可以产生 使膜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上组装更多的含糖聚合物来促进通讯 通过细胞表面聚合物的减少，或相反，抑制细胞表面的通讯。在这 建议，我们的目标是(1)确定如何通过膜交换信息以及通过膜交换什么类型的信息 (2)确定膜桥的形成如何受内部细胞骨架的控制 和它的调节器；以及(3)确定产生囊泡并将消息传送到 参与细胞。 为了研究这些可能性，我们将使用能够分辨超小型的复杂的新成像技术 细胞特征，比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，可以对细胞进行编程，以在其上组装新的不同类型的聚合物 它们的外膜。一个主要目标是确定从供方发送到接收方的消息的类型 细胞。除了先进的成像方法外，我们还将使用功能强大的下一代技术，这些技术可以 同时识别大量的蛋白质或核酸(即遗传指令)，它们可能是 所传输的消息的。 我们寻求发展的新理解应该在生物医学中具有广泛的相关性。特别是， 侵袭性癌细胞通常会在其外膜上产生并附着数量异常多的含糖聚合物。 因此，我们的研究可以提供新的见解，了解癌症中细胞间通讯如何出错，以及如何 我们可能会进行治疗干预，以正常化和纠正我们细胞之间的信息流。