Basal Progenitor Cells and Eosinophilic Esophagitis

描述(申请人提供)：嗜酸性食管炎(EoE)是一种最近的特征疾病，在过去的十年中发病率迅速增加。它影响所有年龄段的人，偏爱儿童和30-40多岁的成年人。EoE的病因与包括IL-13在内的高水平细胞因子的过敏原/免疫反应有关。持续的炎症会导致组织重塑，包括基底前体细胞的增殖、上皮下纤维化和食道狭窄。虽然目前的治疗方法(如局部应用类固醇)在减轻炎症方面是有效的，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，为了获得新的有效的治疗方法，有必要更好地了解该病的病理生物学。许多证据支持IL-13在EoE的启动和随后的组织重塑中发挥重要作用。IL-13下游靶基因Stat6的基因去除可以缓解基底细胞的增生。然而，IL-13如何在组织重塑过程中调节基础祖细胞仍未被探索。我们先前已经证实，骨形态发生蛋白(BMP)信号调节发育中的食道基底祖细胞的分化。值得注意的是，我们的初步数据表明，在EoE小鼠模型和人类活检中，BMP信号减弱。因此，我们建议确定BMP信号如何改变并参与EoE的病理进展。我们的中心假设是，在EoE组织重塑过程中，IL-13通过抑制BMP信号介导的分化促进了基底细胞的增殖。我们将测试这三个特定的目标：(1)测试在EoE组织重塑过程中抑制BMP信号促进基底细胞增殖的假设。(2)验证IL-13通过上调BMP抑制剂Follistatin促进基底细胞增殖的假说。(3)以卵泡抑素为靶点，合成新化合物，以减轻基底细胞增生。 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.