ENDOTHELIAL ALPHA V INTEGRIN COMPLEXES MODULATED ACTIN CYTOSKELETAL ORGANIZATION

内皮 α V 整合素复合物调节肌动蛋白细胞骨架组织

• 批准号: 8363823
• 负责人: Dean Sheppard
• 金额: $ 0.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363823
• 关键词: Actins; Acute; Acute Lung Injury; Amino Acid Sequence; Binding; Biological; Blood; Blood Vessels; Cardiovascular system; Cell Line; Cell Surface Receptors; Cell physiology; Complex; Cytoskeletal Modeling; Cytoskeleton; DNA Sequence Rearrangement; Disease; Edema; Endothelium; Funding; Grant; Inflammatory; Integrin alphaV; Integrin alphaVbeta3; Integrins; Liquid substance; Mass Spectrum Analysis; Mediating; Mediator of activation protein; National Center for Research Resources; Organ; Pathway interactions; Peptide Sequence Determination; Permeability; Plasma; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resources; Sepsis; Source; Stress Fibers; Thrombin; United States National Institutes of Health; arm; cost; protein complex; response; solute; sphingosine 1-phosphate

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. Integrins are cell surface receptors that serve a number of basic cellular functions. One of these functions, which is relevant to the organ edema that occurs in inflammatory diseases like acute lung injury, is the regulation of passage of fluid and solute across the endothelium, the layer of cells lining blood vessels throughout the circulatory system. The Sheppard lab has recently demonstrated that alpha-v integrins modulate endothelial permeability by organizing the actin cytoskeleton. Specifically, alpha-v beta-3 integrin is necessary for rearrangement of actin into cortical distribution that increases vascular barrier strength in response to sphingosine 1-phosphate, a plasma borne barrier-enhancing molecule; on the other hand, alpha-v beta-5 is required for organization of the cytoskeleton into stress fibers that decrease barrier strength in response to thrombin, a blood borne mediator of increased blood vessel leakiness. Our objective is to identify the constituents of the protein complexes associated with these integrins. An ideal approach in this regard is to employ mass spectrometry, where biochemically isolated integrin complexes can be submitted to mass spectrometric sequencing for protein discovery. With this unbiased approach, the distinct actin binding and/or modulatory proteins associated with these two integrins may be identified and studied further to understand how they modulate actin organization. Armed with this powerful information, we may further dissect pathways mediating the opposing biological response of these two integrins and target specific points along their respective pathways as potential treatments for organ edema in the setting of sepsis and other acute inflammatory diseases.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 整合素是具有许多基本细胞功能的细胞表面受体。 这些功能之一与急性肺损伤等炎症性疾病中发生的器官水肿相关，是对液体和溶质在整个内皮中的传递的调节，这是整个循环系统的细胞层。 Sheppard Lab最近证明，α-V整联蛋白通过组织肌动蛋白细胞骨架来调节内皮渗透性。 具体而言，α-Vβ-3整联蛋白对于肌动蛋白重排成皮质分布是必需的，这会增加血管屏障强度，以响应鞘氨醇1-磷酸盐，这是血浆传播的屏障增强分子。另一方面，将细胞骨架组织成压力纤维需要α-V Beta-5，从而降低了势凝结的屏障强度，凝血酶是血管泄漏增加的血液传播介质。 我们的目标是确定与这些整合素相关的蛋白质复合物的成分。 在这方面，一种理想的方法是采用质谱法，可以将生化分离的整联蛋白复合物提交给质谱测序以进行蛋白质发现。 通过这种公正的方法，可以进一步识别并研究与这两个整合蛋白相关的独特肌动蛋白结合和/或调节蛋白，以了解它们如何调节肌动蛋白组织。 有了这些强大的信息，我们可能会进一步剖析介导这两个整合素的相对生物学反应，并沿其各自的途径靶向特定点，作为在脓毒症和其他急性炎性疾病的情况下的潜在器官水肿的潜在治疗方法。