Basal Progenitor Cells and Eosinophilic Esophagitis

描述（由申请方提供）：嗜酸性食管炎（EoE）是一种最近表征的疾病，在过去十年中发病率迅速增加。它影响所有年龄段的人，尤其是30- 40岁的儿童和成人。EoE的病因学与过敏原/免疫反应有关，其特征在于高水平的细胞因子，包括IL-13。长期炎症导致组织重塑，包括基底祖细胞增生、上皮下纤维化和食管狭窄。虽然目前的疗法（例如局部类固醇应用）在减少炎症方面是有效的，但它们对现有组织重塑的影响在很大程度上是未知的。因此，更好地了解疾病的病理生物学是必要的，以获得新的有效的治疗。多种证据支持IL-13在EoE的启动和随后的组织重塑中起重要作用。IL-13的下游靶点Stat 6的遗传去除可抑制基底细胞增生。然而，IL-13如何在组织重塑过程中调节基底祖细胞仍然未被探索。我们以前建立了骨形态发生蛋白（Bmp）信号调节分化的基础祖细胞在发展中的食管。值得注意的是，我们的初步数据表明，BMP信号在EoE小鼠模型和人类活检中减少。因此，我们建议确定BMP信号是如何改变和参与病理进展的EoE。我们的中心假设是IL-13通过抑制EoE组织重塑过程中Bmp信号介导的分化促进基底细胞增生。我们将测试这三个具体目标：（1）测试抑制BMP信号传导促进EoE组织重塑过程中基底细胞增生的假设。(2)检验IL-13通过上调Bmp抑制剂Follistatin促进基底细胞增生的假设。(3)用新型化合物靶向卵泡抑素以减弱基底细胞增生。 该项目有望为基础祖细胞分化提供新的遗传和分子机制。通过研究EoE动物模型和人类活检中的BMP信号传导获得的见解将为将这些发现转化为临床奠定重要基础。

DESCRIPTION (provided by applicant): Eosinophilic esophagitis (EoE) is a recently characterized disease that has rapidly increased in incidence over the past decade. It affects people at all ages with a preference in children and adults in their 30-40s. The etiology of EoE has been linked to allergen/immune reactions with characterized high levels of cytokines including IL-13. Prolonged inflammation leads to tissue remodeling including hyperplasia of basal progenitor cell, subepithelial fibrosis and stricture of the esophagus. Although current therapies (e.g. topical steroid application) are effective in reducing inflammation, their effects n existing tissue remodeling are largely unknown. Therefore a better understanding of the pathobiology of the disease is necessitated for deriving novel effective treatment. Multiple lines of evidence support that IL-13 plays important roles in the initiation of EoE and subsequent tissue remodeling. Genetic removal of Stat6, downstream target of IL-13 alleviates basal cell hyperplasia. However, how IL-13 regulates basal progenitor cells during tissue remodeling remains unexplored. We previous established that Bone morphogenetic protein (Bmp) signaling regulates the differentiation of basal progenitor cells in the developing esophagus. Significantly, our preliminary data suggest Bmp signaling is diminished in EoE mouse models and human biopsies. We therefore propose to determine how Bmp signaling is altered and participates in the pathological progression of EoE. Our central hypothesis is that IL-13 promotes basal cell hyperplasia through the inhibition of Bmp signaling-mediated differentiation during EoE tissue remodeling. We will test these three specific aims: (1) To test the hypothesis that suppressed Bmp signaling promotes basal cell hyperplasia during EoE tissue remodeling. (2) To test the hypothesis that IL-13 promotes basal cell hyperplasia by upregulating the Bmp inhibitor Follistatin. (3) To target Follistatin with novel compounds for attenuating basal cell hyperplasia. This project is expected to provide novel genetic and molecular mechanisms of basal progenitor cell differentiation. The insights gained through studying Bmp signaling in EoE animal models and human biopsies will lay an important foundation for translating these findings into the clinic.