Characterization of the Role of NUCB2 in Asthma Pathogenesis

NUCB2 在哮喘发病机制中作用的表征

• 批准号: 8746634
• 负责人: Stewart Levine
• 金额: $ 16.49万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746634
• 关键词: Aminopeptidase; Asthma; Binding Proteins; Cells; Cytoplasmic Vesicles; EF Hand Motifs; Extracellular Space; Goals; Helix-Turn-Helix Motifs; Knockout Mice; Mediating; Mus; Pathogenesis; Protein Binding; Pyroglyphidae; Regulation; Role; TNFRSF1A gene; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Vesicle; Yeasts; extracellular; knockout gene; nucleobindin; trafficking; yeast two hybrid system

Prior studies from our lab have identified a role for NUCB2 in regulating the release of the type I, 55-kDa tumor necrosis factor receptor (TNFR1) from cells to the extracellular space, via a mechanism that may involve the regulation of vesicular trafficking. We utilized yeast two-hybrid screens to identify ARTS-1 (aminopeptidase regulator of tumor necrosis factor shedding) as a TNFR1-binding protein and NUCB2 as an ARTS-1-binding protein. NUCB2 (nucleobindin 2) is an EF-hand, helix-loop-helix protein that binds ARTS-1 and thereby participates in the mechanism mediating the release of TNFR1 to the extracellular space (J Biol Chem 2006; 281: 6860 6873). NUCB2 and ARTS-1 co-localize with TNFR1 in cytoplasmic vesicles and regulate the release of TNFR1 from cells to the extracellular space by two mechanisms, the proteolytic cleavage of TNFR1 ectodomains and the release of TNFR1 exosome-like vesicles (J Clin Invest 2002; 110: 515-526). This project is utilizing NUCB2 knockout mice to investigate the role of this ARTS-1-binding protein in the pathogenesis of experimental murine house dust mite-induced asthma.

我们实验室先前的研究已经确定了NUCB 2在调节I型55 kDa肿瘤坏死因子受体（TNFR 1）从细胞释放到细胞外空间中的作用，通过一种可能涉及调节囊泡运输的机制。 我们利用酵母双杂交筛选，以确定ARTS-1（肿瘤坏死因子脱落的氨肽酶调节剂）作为TNFR 1结合蛋白和NUCB 2作为ARTS-1结合蛋白。 NUCB 2（核结合蛋白2）是EF-手、螺旋-环-螺旋蛋白，其结合ARTS-1，从而参与介导TNFR 1释放到细胞外空间的机制（J Biol Chem 2006; 281：6860 - 6873）。 NUCB 2和ARTS-1与TNFR 1共定位于细胞质囊泡中，并通过两种机制调节TNFR 1从细胞释放到细胞外空间，即TNFR 1胞外域的蛋白水解切割和TNFR 1外泌体样囊泡的释放（J Clin Invest 2002; 110：515-526）。 本项目利用NUCB 2基因敲除小鼠研究ARTS-1结合蛋白在实验性小鼠屋尘螨诱导的哮喘发病机制中的作用。