THE INOSITOL 5-PHOSPHATASE SHIP AND MAST CELL FUNCTION

肌醇 5-磷酸酶运输和肥大细胞功能

• 批准号: 6464029
• 负责人: VANESSA L OTT
• 金额: $ 4.02万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-11-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6464029
• 关键词: antibody receptor; biological signal transduction; enzyme activity; genetically modified animals; immunoglobulin E; inositol phosphates; laboratory mouse; mast cell; phosphatase inhibitor; phosphomonoesterases; protein purification; transfection

Mast cell activation can occur in response to a variety of immunologic and non-immunologic stimuli. However, mast cell function is also subject to regulation by inhibitory receptors that transduce intracellular signals via associated tyrosine phosphatases, SHP-1 and/or SHP-2, and the inositol 5-phosphatase SHIP. Recent studies have demonstrated an important role for SHIP in regulating antigen receptor signaling in lymphoid and myeloid cells. In addition, SHIP is critical for preventing mast cell activation in the absence of antigen. It is presently unknown how SHIP is recruited into sites where it mediates this regulatory function. In preliminary studies, we have identified four novel SHIP- binding membrane glycoproteins in mast cells. We hypothesize that one or more of these glycoproteins may function as inhibitory molecules in the regulation of mast cell function. Furthermore, based on recent studies in B cells, we hypothesize that these and previously defined inhibitory molecules regulate mast cell function via association with SHIP and its effector p62dok. The specific aims of this proposal are to 1) identify novel inhibitory molecules that mediate SHIP activation in mast cells, and 2) define the role of SHIP and p62dok in regulating mast cell function.

肥大细胞活化可响应于多种免疫和非免疫刺激而发生。然而，肥大细胞功能也受到抑制性受体的调节，这些抑制性受体通过相关的酪氨酸磷酸酶SHP-1和/或SHP-2以及肌醇5-磷酸酶SHIP抑制细胞内信号。最近的研究表明，SHIP在调节淋巴细胞和骨髓细胞中的抗原受体信号传导中起重要作用。此外，SHIP对于在缺乏抗原的情况下防止肥大细胞活化至关重要。目前尚不清楚SHIP是如何被募集到介导这种调节功能的位点的。在初步研究中，我们已经确定了肥大细胞中的四种新的SHIP结合膜糖蛋白。我们推测这些糖蛋白中的一种或多种可能在肥大细胞功能的调节中起抑制分子的作用。此外，基于最近在B细胞中的研究，我们假设这些和先前定义的抑制分子通过与SHIP及其效应子p62 dok相关来调节肥大细胞功能。该提案的具体目的是1）鉴定介导肥大细胞中SHIP活化的新型抑制性分子，和2）确定SHIP和p62 dok在调节肥大细胞功能中的作用。