TGF-BETA2 AND IL-4RA PATHWAY INTERACTIONS IN ASTHMA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。导致哮喘和特别是严重哮喘的机制仍然知之甚少。我们实验室以前的工作表明，哮喘患者呼吸道的上皮细胞和成纤维细胞都可能对疾病过程做出贡献。此外，在这些细胞中加入生长因子(转化生长因子β)和Th2(过敏相关)细胞因子--白介素13，会引起一系列可能很重要的反应。对这些因素的反应似乎存在遗传差异。目前的研究将评估IL-13和TCF-Beta单独或联合使用对来自患有和不患有哮喘的受试者的肺上皮细胞和成纤维细胞的影响，这些受试者的遗传背景与这些反应相关。我们将专门讨论这些因素对上皮细胞粘液产生的影响，以及成纤维细胞中一种吸引嗜酸性粒细胞进入呼吸道的有效化学物质(嗜酸性粒细胞趋化因子)。然后，我们将研究导致这些反应的遗传和分子机制。最后，在一系列哮喘受试者和正常对照中，这些途径中的遗传异常的影响也将在临床和生理临床水平上得到解决。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mechanisms driving asthma and particularly severe asthma remain poorly understood. Previous work from our laboratory has suggested that both epithelial cells and fibroblasts from the airways of asthmatic subjects are likely to contribute to the disease process. Further, the addition of a growth factor (transforming growth factor beta) and a Th2 (allergy related) cytokine, Interleukin 13, to these cells induces a variety of responses that are likely to be important. Genetic differences seem to exist in the responses to these factors. The current study will evaluate the effect of IL-13 and TCF-Beta alone or in combination, on lung epithelial cells and fibroblasts derived from human subjects, with and without asthma, whose genetic background related to these responses is known. We will specifically address the impact of these factors on mucus production in the epithelial cells and a potent chemical that attracts eosinophils to the airways (eotaxin) in fibroblasts. We will then look at the mechanisms, genetic and molecular, that lead to these responses. Finally, the impact of genetic abnormalities in these pathways will also be addressed at the clinical and physiologic clinical level in a range of asthma subjects and normal controls.