GSDMB and mucosal allergic response

这项提议的重点是GSDMB(Gasdermin B)，一个位于染色体17q21上的基因 在几项全基因组关联研究中，该区域与人类哮喘高度相关。 此外，由于携带17q21染色体SNP的哮喘患者GSDMB表达增加， 我们培育了过表达人GSDMB转基因的转基因小鼠。初步 对这些GSDMB转基因小鼠的鉴定表明，它们增加了GSDMB基因的表达 GSDMB调节人支气管上皮的促炎和重塑途径 体外高表达GSDMB的细胞。哮喘患者肺组织GSDMB功能的研究 这项拨款建议将通过在PI的实验室中开发独特的试剂来促进，这些试剂不是 商业上可获得的(例如，人GSDMB cre激活的转基因小鼠，用于细胞特异性条件过... 转基因全长GFP标记和未标记人GSDMB的体外表达 研究；腺病毒人GSDMB构建在体外转染人肺支气管上皮细胞)。 我们还将研究GSDMB在人肺体外表达如何影响支气管扩张， 使用由我的合作研究员库尔滕博士开发的新的分析方法来研究支气管收缩和呼吸道重塑。 使用这些新的方法来研究GSDMB在人肺中的功能以及 新型试剂和GSDMB突变小鼠的开发将使我们能够检验在体内 GSDMB在肺中的表达有助于炎症和重塑，从而对呼吸道产生影响 响应性。 PAS-15-055：高优先级免疫学补助金(R01)。这项拨款是为了响应PAS-15- 055，其请求解决分子上的先天和适应性免疫统一性的研究建议， 细胞、生物体和系统层面(我们在GSDMB研究中做到了这一点)。此外，提案还包括 要求使用创新的动物模型(我们已经产生了一种新的有条件的GSDMB转基因 小鼠)，以及人类免疫系统的研究(我们研究严重哮喘患者的人肺) 与列出的两个重要主题相关，即人类粘膜免疫学和调节机制 在健康和严重哮喘的呼吸道中。

The focus of this proposal is on GSDMB (gasdermin B) a gene on chromosome 17q21, a chromosomal region which has been highly linked to human asthma in several genome wide association studies. Moreover, as asthmatics with a SNP linked to chromosome 17q21 have increased expression of GSDMB, we generated transgenic mice which overexpress the human GSDMB transgene. Preliminary characterization of these GSDMB transgenic mice demonstrate that they have increased expression of the same GSDMB regulated pro-inflammatory and remodeling pathways we noted in human bronchial epithelial cells overexpressing GSDMB in vitro. The investigation of the function of GSDMB in the lung in asthma in this grant proposal will be facilitated by the development of unique reagents in the PI’s lab that are not commercially available (e.g. human GSDMB cre activated transgenic mice for cell specific conditional over- expression of the transgene; full length GFP labeled and unlabeled human GSDMB construct for in vitro studies; adenoviral human GSDMB construct to transfect into human lung bronchial epithelial cells in vitro). We will also study how GSDMB expressed in human lung ex vivo influences bronchodilation, bronchoconstriction, and airway remodeling using novel assays developed by my co-investigator Dr Kurten. The use of these novel approaches to study the function of GSDMB in human lung, as well as the development of novel reagents and GSDMB mutant mice will allow us to test the hypothesis that in vivo GSDMB expression in lung contributes to inflammation, and remodeling, with resultant effects on airway responsiveness. PAS-15-055: High Priority Immunology Grants (R01). This grant is submitted in response to PAS-15- 055 which requests research proposals that addresses innate and adaptive imm unity at the molecular, cellular, organism, and systems level (which we do in this study of GSDMB). In addition, proposals are requested that use innovative animal models (we have generated a novel conditional GSDMB transgenic mouse), and studies of the human immune system (we study human lung from severe asthmatics) with relevance to two topics of importance listed, i.e. human mucosal immunology and regulatory mechanisms in healthy vs severe asthmatic airways.