Stard7, a Novel Inhibitor of Allergic Lung Disease

描述（由申请人提供）：不可渗透的上皮屏障为与环境广泛接触的器官（包括皮肤、肺和肠道）提供了关键的第一道防线。越来越多的证据表明，上皮屏障完整性的丧失促进过敏原渗透，局部致敏，并最终导致过敏性疾病的持续存在。阐明上皮屏障结构/功能的早期变化（即， 与致敏作用一致）可能会发现新的治疗靶点，并为目前针对抑制炎症的治疗提供替代疗法。在本申请中，我们提供了一种新的保护途径的证据，该途径以脂质转移蛋白Stard 7为中心，促进屏障形成并抑制炎症。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，Stard 7的表达下调。我们已经破坏了小鼠中的Stard 7基因座，并表明Stard 7的单倍不足（即在Stard 7 +/-小鼠中）导致自发性皮炎、肠上皮细胞耐受性丧失和夸大的实验性哮喘。本申请的重点是鉴定Stard 7在过敏性肺病中保护作用的分子机制。对Stard 7 +/-小鼠的初步分析表明：（1）Stard 7的保护作用与上皮细胞和树突状细胞（DC）中的表达有关，（2）Stard 7的免疫抑制作用与上皮细胞和树突状细胞（DC）中的表达有关。 在上皮细胞和DC的细胞核中检测到，以及（3）Stard 7与包括PPAR的核转录复合物缔合。这些关键发现导致了中心假设，即Stard 7是一种新的核辅因子，其促进参与上皮屏障功能的基因的表达并抑制参与DC活化的基因的表达。提出了三个具体的目的来测试这一假设在肺组织中的WT小鼠和基因靶向小鼠，其中Stard 7表达被选择性删除在呼吸道上皮细胞（Stard 7 epi-/）或DC（Stard 7 DC-/-）。具体目标1将确定上皮屏障功能是否需要Stard 7。具体目标2将确定Stard 7是否是上皮屏障基因表达的核共激活因子。具体目标3将确定Stard 7是否是DC激活的调节剂。总的来说，这些研究将通过鉴定介导Stard 7的细胞特异性屏障增强和抗炎作用的细胞信号传导途径和靶基因，为这种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.