Stard7, a Novel Inhibitor of Allergic Lung Disease

描述(由申请人提供)：不透水的上皮屏障为广泛与环境接触的器官提供了关键的第一道防线，包括滑雪、肺和肠道。越来越多的证据表明，上皮屏障完整性的丧失促进了过敏原的渗透、局部敏化，并最终导致过敏性疾病的持久性。阐明上皮屏障结构/功能的早期变化(即先于或 与致敏同时进行的治疗)可能会发现新的治疗靶点，并为目前用于抑制炎症的药物提供替代疗法。在这一应用中，我们为以脂转移蛋白Stard7为中心的一种新的保护途径提供了证据，该途径促进屏障形成和抑制炎症。我们的初步研究结果表明，在哮喘患者和特应性皮炎小鼠模型中，Stard7的表达下调。我们已经扰乱了小鼠的Stard7基因座，并表明Stard7单倍体不足(即在Stard7+/-小鼠中)会导致自发性皮炎、肠道上皮细胞耐受性丧失和夸大实验性哮喘。这项应用侧重于鉴定Stard7在变态反应性肺部疾病中保护作用的分子机制。对Stard7+/-小鼠的初步分析表明：(1)Stard7的保护作用与上皮细胞和树突状细胞(DC)的表达有关，(2)Stard7 在上皮细胞和树突状细胞的细胞核中检测到；(3)Stard7与包括PPAR的核转录复合体有关。这些关键发现导致了中心假说，即Stard7是一种新的核辅助因子，它促进参与上皮屏障功能的基因的表达，并抑制参与DC激活的基因的表达。在WT小鼠和基因靶向小鼠的肺组织中，Stard7的表达在呼吸道上皮细胞(Stard7epi-/)或DC(Stard7DC-/-)中选择性缺失，提出了三个特定的目标来验证这一假说。特定的目标1将确定Stard7是否是上皮屏障功能所必需的。特异性目标2将确定Stard7是否是上皮屏障GNE表达的核共激活因子。具体目标3将确定Stard7是否是DC激活的调节器。总之，这些研究将通过识别细胞信号通路(S)和介导Stard7细胞特异性屏障增强和抗炎作用的靶基因，为这一保护途径提供重要的新见解。

DESCRIPTION (provided by applicant): An impermeable epithelial barrier provides a critical first line of defense for organs that interface extensively with the environment, including the ski, lung, and gut. There is growing evidence that loss of epithelial barrier integrity facilitates allergen penetration, local sensitization and, ultimately, persistence of allergic disease. Elucidation of early changes in epithelial barrier structure/function (i.e. changes that precede or coincide with sensitization) may uncover new therapeutic targets and provide alternative therapies to those currently directed toward suppressing inflammation. In this application, we provide evidence for a novel protective pathway, centered on the lipid transfer protein Stard7, which promotes barrier formation and suppresses inflammation. The results of our preliminary studies indicate that expression of Stard7 is downregulated in patients with asthma and in a mouse model of atopic dermatitis. We have disrupted the Stard7 locus in mice and show that haploinsufficiency for Stard7 (i.e. in Stard7+/- mice) leads to spontaneous dermatitis, loss of tolerance in gut epithelia and exaggerated experimental asthma. This application focuses to identification of the molecular mechanisms underlying the protective effect of Stard7 in allergic lung disease. Preliminary analyses of Stard7+/- mice suggest that (1) the protective effect of Stard7 is associated with expression in both epithelial cells and dendritic cells (DCs), (2) Stard7 is detected in nuclei of epithelial cells and DCs and (3) Stard7 associates with nuclear transcriptional complexes that include PPAR. These key findings lead to the central hypothesis that Stard7 is a novel nuclear co-factor that promotes expression of genes involved in epithelial barrier function and suppresses expression of genes involved in activation of DCs. Three specific aims are proposed to test this hypothesis in lung tissues of WT mice and gene-targeted mice in which Stard7 expression is selectively deleted in respiratory epithelial cells (Stard7epi-/) or DCs (Stard7DC-/-). Specific aim 1 will determine if Stard7 is required for epithelial barrier function. Specific aim 2 will determine if Stard7 is a nuclear co-activator of epithelial barrier gne expression. Specific aim 3 will determine if Stard7 is a modulator of DC activation. Collectively these studies will provide important, new insight into this protective pathway by identifying cells signaling pathway(s) and target genes that mediate the cell-specific barrier-enhancing and anti-inflammatory actions of Stard7.