LOCALIZED CAMP SIGNALS IN ENDOTHELIAL CELLS

内皮细胞中的局部 CAMP 信号

• 批准号: 8362509
• 负责人: THOMAS C RICH
• 金额: $ 1.05万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362509
• 关键词: Buffers; Camping; Cell membrane; Cells; Cyclic AMP; Cyclic Nucleotides; Development; Diffusion; Endothelial Cells; Funding; Gene Expression; Goals; Grant; Laboratories; Lung; Measurement; Measures; Methods; Modeling; Movement; National Center for Research Resources; Principal Investigator; Process; Research; Research Infrastructure; Resolution; Resources; Second Messenger Systems; Signal Pathway; Signal Transduction; Source; Techniques; Testing; United States National Institutes of Health; Work; base; cell type; cost; phosphoric diester hydrolase; second messenger

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term goal of our laboratory is to understand the mechanisms by which information is encoded within second messenger signals, including Ca2+ and cAMP. These signaling pathways are known to regulate diverse processes including cellular excitability, proliferation, and gene expression. Our understanding of Ca2+ signals has increased dramatically over the last 30 years, primarily due to the development of single-cell methods for measuring intracellular Ca2+. Our understanding of cAMP signals, however, has lagged behind, largely due to the lack of high-resolution, single-cell measurement techniques. Only recently have reliable approaches for measuring cAMP signals in single cells been developed. These approaches have provided an unprecedented view of cyclic nucleotide signals near the plasma membranes of several cell types. We have used these approaches to provide evidence suggesting that the effective diffusion coefficient of cAMP is considerably slower than had been previously thought (~10,000-fold slower movement than by free diffusion alone). In addition, elegant studies demonstrated that compartmentalized cAMP signals are critical for barrier function in pulmonary microvascular endothelial cells (PMVECs). Based upon these studies, we propose testing the following working hypothesis: phosphodiesterase activity, buffering, and anomalously slow cAMP diffusion localize cAMP signals in pulmonary microvascular endothelial cells.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们实验室的长期目标是了解第二信使信号（包括 Ca2+ 和 cAMP）中信息编码的机制。已知这些信号通路可调节多种过程，包括细胞兴奋性、增殖和基因表达。过去 30 年来，我们对 Ca2+ 信号的了解急剧增加，这主要归功于测量细胞内 Ca2+ 的单细胞方法的发展。 然而，我们对 cAMP 信号的理解却滞后，这很大程度上是由于缺乏高分辨率、单细胞测量技术。直到最近才开发出测量单细胞中 cAMP 信号的可靠方法。这些方法为几种细胞类型质膜附近的环核苷酸信号提供了前所未有的视角。我们使用这些方法提供的证据表明，cAMP 的有效扩散系数比之前认为的要慢得多（比单独自由扩散的运动慢约 10,000 倍）。此外，出色的研究表明，区室化的 cAMP 信号对于肺微血管内皮细胞 (PMVEC) 的屏障功能至关重要。基于这些研究，我们建议测试以下工作假设：磷酸二酯酶活性、缓冲和异常缓慢的 cAMP 扩散将 cAMP 信号定位在肺微血管内皮细胞中。