New insights into extracellular signal transduction

项目总结 细胞最基本的特性之一是能够将信号传递给其他细胞 细胞和周围环境。公认的细胞信号模式包括直接 通过膜受体和配体的细胞-细胞相互作用和可溶性因子的释放，如 作为生长因子、细胞因子和趋化因子。最近描述的细胞外小泡 (EV)现在也被认为是细胞信号的重要中介，允许细胞交换 蛋白质、类脂和遗传物质。EV由几乎所有类型的细胞分泌，以EV为基础 通讯依赖于小泡将生物活性分子运送到其他细胞的能力。这个 电动汽车生物学领域正在迅速发展和扩大，影响到几乎所有的生物医学学科， 从肿瘤学和产科到传染病和干细胞生物学。细胞释放电动汽车注意事项 不仅在培养中，而且在体内也是如此，各种类型的囊泡已经被分离和分析 从几乎所有的体液中提取，这导致了基于EV的液体活组织检查可以使用的假设 用于诊断。然而，尽管令人兴奋，并有数百种关于电动汽车的新出版物在 最近，关于它们的功能的几个基本假设仍然没有得到实验验证。一个 电动汽车研究中的主要挑战是脱落小泡中巨大的、往往被低估的多样性。 推动电动汽车生物学和应用的许多障碍源于无法 将复杂的囊泡群体分成具有特定大小、成分和 生物发生途径。微囊泡(MVS)是肠道病毒的一种亚型，由细胞直接排出 质膜向外萌发。它们存在于生物体液中，似乎是 参与多种生理和病理过程。然而，还有很多事情是未知的。 认为这些小泡的生物发生和作为信号媒介的作用。在这里，我们建议 对特定针对MVS的分子货物进行分类并确定新的调节剂的策略 货物装载的数量。我们还打算询问GTPase调节的细胞信号通路 调节MV的释放。最后，我们将研究MVS与内皮细胞上受体的相互作用 细胞和随后的信号通路在受体细胞中被激活。这些研究将提供 对信号转导中一个快速发展的前沿以及分子基础的新见解 各种疾病。

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.