New insights into extracellular signal transduction

细胞外信号转导的新见解

• 批准号: 10566506
• 负责人: CRISLYN D'SOUZA-SCHOREY
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566506
• 关键词: ADP-ribosylation factor 6; Actomyosin; Address; Affect; Attention; Bacterial Infections; Biochemical; Biogenesis; Biological; Biology; Blood Vessels; Body Fluids; CRISPR/Cas technology; Cardiovascular Diseases; Catalogs; Cell Communication; Cell Line; Cell membrane; Cell surface; Cells; Classification; Clinical; Communicable Diseases; Communication; Complex; Cues; Diabetes Mellitus; Diagnostic; Discipline; Discipline of obstetrics; Disease; Endosomes; Endothelial Cells; Environment; Fibrinogen; Functional disorder; Genetic Materials; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Investigation; Knock-out; Ligands; Ligase; Link; Lipids; Liquid substance; Malignant Neoplasms; Mediating; Mediator; Membrane; Molecular; Morphogenesis; Nature; Neurodegenerative Disorders; Oncology; Onset of illness; Organism; Pathologic Processes; Pathway interactions; Phenotype; Physiological Processes; Physiology; Play; Population; Positioning Attribute; Process; Property; Proteins; Proteome; Publications; Recycling; Research; Role; Signal Pathway; Signal Transduction; Testing; Vascular Endothelial Growth Factors; Vesicle; cell behavior; cell type; chemokine; cytokine; exosome; experience; extracellular; extracellular vesicles; frontier; in vivo; insight; intercellular communication; interest; liquid biopsy; microvesicles; neoplastic cell; novel; novel therapeutic intervention; receptor; release factor; research and development; rho; rho GTP-Binding Proteins; stem; stem cell biology; trafficking; vesicular release

PROJECT SUMMARY One of the most fundamental properties of cells is the ability to transduce signals to other cells and the surrounding environment. Well recognized modes of cellular signaling include direct cell-cell interactions via membrane receptors and ligands and the release of soluble factors, such as growth factors, cytokines and chemokines. The more recently described extracellular vesicle (EV) is now also considered as an important mediator of cell signaling, allowing cells to exchange proteins, lipids and genetic material. EVs are secreted from nearly all cell types and EV-based communication relies on the ability of vesicles to deliver bioactive molecules to other cells. The field of EV biology is rapidly evolving and expanding, affecting almost all biomedical disciplines, from oncology and obstetrics to infectious diseases and stem cell biology. Cells release EVs not only in culture but also in vivo, and diverse types of vesicles have been isolated and analyzed from almost all bodily fluids, leading to the postulation that EV-based liquid biopsies can be used for diagnostics. However, despite the excitement and hundreds of new publications on EVs in recent past, several basic hypotheses regarding their function remain experimentally untested. A major challenge in EV research is the huge and often underappreciated diversity in shed vesicles. Many of the impediments to advance EV biology and application, stem from the inability to separate a complex population of vesicles into subclasses of particular sizes, compositions, and biogenesis pathways. Microvesicles (MVs) are an EV subtype which are shed by the direct outward budding of the plasma membrane. They are present in biological fluids and appear to be involved in multiple physiological and pathological processes. However, much remains unknown regarding the biogenesis and role of these vesicles as signaling mediators. Here we propose strategies to catalog molecular cargoes targeted specifically to MVs and identify new regulators of cargo loading. We also aim to interrogate GTPase-regulated cell signaling pathways that regulate MV release. Finally, we will examine the interactions of MVs with receptors on endothelial cells and consequent signaling pathways activated in the recipient cell. These studies will provide new insights into a rapidly evolving frontier in signal transduction, as well as the molecular basis of various diseases.

项目概要 细胞最基本的特性之一是将信号传递给其他细胞的能力 细胞和周围环境。公认的细胞信号传导模式包括直接 通过膜受体和配体的细胞间相互作用以及可溶性因子的释放，例如 如生长因子、细胞因子和趋化因子。最近描述的细胞外囊泡 (EV) 现在也被认为是细胞信号传导的重要介质，允许细胞交换 蛋白质、脂质和遗传物质。 EV 几乎由所有细胞类型和基于 EV 的细胞分泌 通讯依赖于囊泡将生物活性分子传递到其他细胞的能力。这 EV生物学领域正在迅速发展和扩展，影响几乎所有生物医学学科， 从肿瘤学和产科到传染病和干细胞生物学。电池不释放 EV 不仅在培养物中，而且在体内，并且已经分离和分析了多种类型的囊泡 来自几乎所有体液，导致可以使用基于 EV 的液体活检的假设 用于诊断。然而，尽管人们兴奋不已，并且有数百篇有关电动汽车的新出版物 最近，关于其功能的几个基本假设仍未经过实验检验。一个 EV 研究的主要挑战是脱落囊泡的巨大且经常被低估的多样性。 推进电动汽车生物学和应用的许多障碍源于无法 将复杂的囊泡群分成具有特定大小、组成和特征的子类 生物发生途径。微泡 (MV) 是一种 EV 亚型，由直接 质膜向外出芽。它们存在于生物体液中并且似乎 参与多种生理和病理过程。然而，还有很多未知 关于这些囊泡作为信号传导介质的生物发生和作用。在这里我们建议 对专门针对 MV 的分子货物进行编目并确定新监管机构的策略 货物装载。我们还旨在探究 GTPase 调节的细胞信号通路 调节 MV 释放。最后，我们将检查 MV 与内皮细胞受体的相互作用 细胞和随后在受体细胞中激活的信号通路。这些研究将提供 对信号转导快速发展的前沿以及分子基础的新见解 各种疾病。