New frontiers in extracellular signaling

细胞外信号传导的新领域

• 批准号: 9910427
• 负责人: RICHARD A. CERIONE
• 金额: $ 58.03万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910427
• 关键词: Address; Attention; Bacteria; Biochemical; Biogenesis; Biological; Biological Process; Cell Communication; Cell Proliferation; Cells; Cues; Disease; Enzymes; Epidermal Growth Factor Receptor; Event; Family; Family member; Generations; Glutaminase; Glutamine; Goals; Immune response; Laboratories; Learning; Link; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; National Institute of General Medical Sciences; Nature; Neurodegenerative Disorders; Neurons; Normal Range; Organism; Outcome; Parents; Pathologic; Physiological; Physiological Processes; Play; Positioning Attribute; Process; Proteins; RNA; Research Support; Role; Secretory Vesicles; Signal Pathway; Signal Transduction; Structure; Therapeutic Intervention; Viral; Work; cancer cell; cell type; embryonic stem cell; exosome; extracellular; extracellular vesicles; falls; frontier; insight; intercellular communication; laboratory experience; microvesicles; mouse model; natural Blastocyst Implantation; novel; research and development; rho GTP-Binding Proteins; stem cell biology; trophoblast

Abstract- The overall goals of our NIGMS-supported research have been to determine how EGF receptor (EGFR) family members and Rho GTPases trigger signaling pathways essential for normal biological processes and, when de-regulated, give rise to disease states. Our work has relied upon a combination of biochemical, cell biological, and structural approaches, as well as more recently, mouse models. These efforts led to our discovery of a novel signaling-pathway that results in the activation of a key metabolic enzyme, glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and is essential for highly proliferative cells including cancer cells. We then discovered that an important outcome of these metabolic changes is the generation of microvesicles (MVs), a specific subset of non-classical secretory vesicles that fall within the larger family of extracellular vesicles (EVs). MVs, together with the other major class of EVs, exosomes, are now garnering a great deal of attention because of their roles in a wide range of normal physiological processes as well as in different diseases. They have been linked to biological activities that span the evolutionary spectrum from bacteria to viral infectivity, and to a diversity of physiological processes in higher organisms including the immune response and neuronal function, as well as being connected to diseases such as cancer and neurodegenerative disorders. Moreover, EVs have also been implicated in stem cell biology, with our laboratory recently discovering that MVs shed from embryonic stem cells play a critical role in activating trophoblasts, an essential step in embryo implantation. Still, we are at an early stage in understanding the actions of these novel modes of information transfer between cells. In particular, there is a critical need to define the biochemical and signaling mechanisms that underlie MV functions. Among the important questions surrounding this exciting field include what are the signaling mechanisms responsible for the biogenesis of MVs by cancer cells where their actions have been most heavily studied, as well as the specific cues that dictate the loading of MVs with protein and RNA cargo, and whether they are conserved across different cell types. Moreover, we need to learn much more about the nature of the signals that trigger the shedding of MVs from their parental (donor) cells, thus enabling them to engage and transfer protein and RNA cargo to their target cells. Addressing these questions will require a number of new lines of research and development, as they represent an important and rapidly emerging frontier in signal transduction. Given our laboratory's experience and expertise, we are well positioned to define the signaling mechanisms responsible for the biogenesis and function of this novel form of intercellular communication, which ultimately should yield new insights into fundamentally important biological processes, as well as the molecular basis of various diseases and pathological disorders.

摘要-我们 NIGMS 支持的研究的总体目标是确定 EGF 受体如何 (EGFR) 家族成员和 Rho GTPases 触发正常生物必需的信号通路 过程，当放松管制时，就会引起疾病状态。我们的工作依赖于以下因素的结合 生物化学、细胞生物学和结构方法，以及最近的小鼠模型。这些 我们的努力导致我们发现了一种新的信号传导途径，该途径可激活关键代谢 谷氨酰胺酶 C (GAC)，它催化谷氨酰胺代谢的第一步，对于 高度增殖的细胞，包括癌细胞。然后我们发现这些的一个重要成果 代谢变化是微泡 (MV) 的产生，微泡是非经典分泌的一个特定子集 属于细胞外囊泡 (EV) 大家族的囊泡。与其他主要MV一起 EV 类外泌体由于其在广泛领域中的作用而受到广泛关注 正常生理过程以及不同疾病的情况。它们与生物学有关 跨越从细菌到病毒感染性以及多种生物进化谱的活动 高等生物体的生理过程，包括免疫反应和神经元功能，如 以及与癌症和神经退行性疾病等疾病有关。此外，电动汽车 也与干细胞生物学有关，我们的实验室最近发现 MV 脱落 来自胚胎干细胞的在激活滋养层细胞中发挥着关键作用，滋养层细胞是胚胎发育过程中的一个重要步骤 植入。尽管如此，我们仍处于理解这些新颖模式的作用的早期阶段。 细胞之间的信息传递。特别是，迫切需要定义生化和 MV 功能背后的信号传导机制。围绕此问题的重要问题包括 令人兴奋的领域包括负责癌症 MV 生物发生的信号传导机制是什么 对其行为进行了最深入研究的细胞，以及决定其行为的具体线索 MV 中蛋白质和 RNA 的负载，以及它们在不同细胞类型中是否保守。 此外，我们需要更多地了解触发 MV 脱落的信号的性质 从它们的亲代（供体）细胞中分离出来，从而使它们能够接合蛋白质和 RNA 货物并将其转移到它们的 靶细胞。解决这些问题需要一系列新的研究和开发， 因为它们代表了信号转导领域一个重要且快速新兴的前沿领域。鉴于我们实验室的 经验和专业知识，我们有能力定义负责的信号机制 这种新型细胞间通讯的生物发生和功能，最终应该产生 对根本重要的生物过程以及各种分子基础的新见解 疾病和病理障碍。