A NOVEL RECEPTOR: 14-3-3 AXIS REGULATES CELL FUNCTION

一种新型受体：14-3-3 轴调节细胞功能

• 批准号: 6927125
• 负责人: ANGEL F LOPEZ
• 金额: $ 22.5万
• 依托单位: INSTITUTE OF MEDICAL AND VET SCIENCE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927125
• 关键词: SDS polyacrylamide gel electrophoresis; binding proteins; biological signal transduction; cell component structure /function; clinical research; colony stimulating factor; cytokine receptors; flow cytometry; genetically modified animals; human tissue; immunoprecipitation; integrins; interleukin 3; interleukin 5; laboratory mouse; mass spectrometry; myeloid stem cell; phosphatidylinositol 3 kinase; phosphorylation; platelets; purinergic receptor; receptor; reversed phase chromatography; serine; western blottings

DESCRIPTION (provided by applicant): The overall aim of this application is the molecular and functional characterization of a novel receptor-initiated signaling pathway we have identified in hematopoietic cells. Activation of this pathway is triggered by engagement of the GM-CSF/IL-3/IL-5 receptors in myeloid cells and of the GPIb-IX-V receptor complex in platelets. A unique feature of this pathway is its initiation by receptor site-specific serine phosphorylation and recruitment of phosphoserine-binding adaptor protein 14-3-3. The specific aims of this proposal are to: 1. Biochemically characterize the interactions between receptors, 14-3-3 and PI 3-kinase seeking to determine the assemblage and architecture of these complexes. 2. Determine the functional significance of these complexes in myeloid cells and platelets in vitro. 3. Determine the functional significance of this pathway in vivo using specific animal models. This proposal has the long-term aim of understanding the mechanism of activation of myeloid cells and platelets, two hematopoietic cell types essential for a living organism. In the case of myeloid cells, these studies have the potential to unravel the poorly understood survival and "primary" effects of GM-CSF, IL-3 and IL-5, which the body utilizes to combat invading pathogens. In platelets, these studies should provide essential knowledge on the activation of the receptor GPIb-IX-V complex and its role in maintaining homeostasis. Importantly, activation of the novel signaling pathway we have uncovered is likely to be involved in debilitating human pathologies and its characterization may provide novel targets for interfering with its assemblage for therapeutic purposes. In myeloid cells, abnormal activation of the GM-CSF, IL-3 and IL-5 receptors has been implicated in myeloid leukaemias and chronic inflammatory diseases such as asthma and rheumatoid arthritis. In platelets, abnormal activation of the GPIb-LX-V complex is involved in thrombosis that triggers unstable angina, myocardial infarction and stroke, the leading combined causes of death in the western world.

描述（由申请人提供）：该应用的总体目的是我们在造血细胞中发现的新型受体引起的信号通路的分子和功能表征。该途径的激活是由髓样细胞中的GM-CSF/IL-3/IL-5受体的参与而引起的，而血小板中的GPIB-IX-V受体复合物则触发。该途径的一个独特特征是它通过受体位点特异性丝氨酸磷酸化的启动和磷脂结合衔接蛋白的募集14-3-3。该提案的具体目的是： 1。从生化表征受体之间的相互作用，即14-3-3和PI 3-激酶，以确定这些复合物的组合和结构。 2。确定体外这些复合物在髓样细胞和血小板中的功能意义。 3。使用特定动物模型在体内确定该途径的功能意义。 该建议的长期目的是了解髓样细胞和血小板的激活机制，这是生物体必不可少的两种造血细胞类型。在髓样细胞的情况下，这些研究可能会揭示GM-CSF，IL-3和IL-5的生存不足和“主要”作用，IL-3和IL-5的作用是人体用来打击入侵的病原体的。在血小板中，这些研究应提供有关受体GPIB-IX-V复合物及其在维持稳态中的作用的基本知识。重要的是，我们发现的新型信号通路的激活很可能与使人类病理的衰弱有关，其表征可能为干扰其用于治疗目的的组装提供新的目标。在髓样细胞中，GM-CSF，IL-3和IL-5受体的异常激活与髓样白血病和慢性炎症性疾病有关，例如哮喘和类风湿关节炎。在血小板中，GPIB-LX-V复合物的异常激活参与血栓形成，这会触发不稳定的绞合绞痛，心肌梗塞和中风，这是西方世界中主要的死亡原因。