New insights into extracellular signal transduction

项目摘要 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。公认的细胞信号传导模式包括直接 通过膜受体和配体的细胞-细胞相互作用以及可溶性因子的释放， 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从几乎所有的细胞类型分泌，并且基于EV的 细胞间通讯依赖于囊泡将生物活性分子传递给其它细胞的能力。的 EV生物学领域正在迅速发展和扩大，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。电池释放EV 不仅在培养中，而且在体内，并且已经分离和分析了不同类型的囊泡 几乎所有的体液，导致假设，基于电动汽车的液体活检可以使用 用于诊断。然而，尽管兴奋和数以百计的新出版物电动汽车在 最近，关于它们的功能的几个基本假设仍然未经实验检验。一 EV研究的主要挑战是脱落囊泡的巨大且常常被低估的多样性。 推进EV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特定大小、组成和 生物合成途径微囊泡（MV）是EV的一种亚型， 质膜向外出芽。它们存在于生物体液中， 参与多种生理和病理过程。然而，仍有许多未知数 关于这些囊泡作为信号介质的生物起源和作用。在这里我们建议 分类专门针对MV的分子货物并识别新调节剂的策略 货物装载。我们的目标还在于询问GTP酶调节的细胞信号通路， 调节MV释放。最后，我们将研究MV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激活。这些研究将提供 新的见解迅速发展的前沿信号转导，以及分子基础 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.