Esophageal tissue aging under homeostatic and inflammatory conditions

项目摘要 食管功能障碍和病理学代表了美国和世界范围内的重大健康负担。 虽然患者年龄是吞咽困难、食管癌和嗜酸性食管炎的既定风险因素， （EoE）相关的上皮下纤维化，我们对食管衰老生物学的理解仍然存在 难以捉摸。在稳态条件下，食管鳞状上皮包括基底室， 增殖细胞在基底上层分化和管腔脱落，促进组织 退款食管上皮中这种确定的增殖/分化梯度的扰动是食管癌的一个特征。 食管病变，包括EoE。虽然BCH的患病率在儿童和成人中几乎相同， 对于活动性EoE患者，初步数据表明，BCH存在于约20%的正常食管上皮中， 成人标本，而在正常儿科标本中检测不到。我们最近 表明自噬（“自噬”）在食管上皮中响应EoE而被激活 炎症，用于限制BCH和嗜酸性粒细胞增多。初步数据表明，自噬通量停滞在 正常情况下的老年食管上皮。此外，老年小鼠中的EoE诱导导致 嗜酸性粒细胞增多和上皮下纤维化减少。最重要的假设是，与年龄相关的 食管上皮细胞自噬通量损害组织稳态并导致年龄相关改变 在EoE表型中。为了验证这一假设，我们将定义mTORC 1/自噬之间的功能关系， 信号和年龄相关的食管基底细胞增生（目的1）;阐明上皮细胞的功能作用， 自噬在年龄相关性EoE纤维化中的作用（目的2）;并研究上皮细胞自噬在EoE纤维化中的作用。 炎症反应的背景下，老化（Am 3）。食管中的衰老生物学代表了 由于了解组织老化的机制，存在重大的知识差距，有可能改善战略 用于诊断、监测和治疗广泛流行的食管疾病，包括EoE和癌症。在这里， 我们研究了上皮细胞自噬作为食管内稳态条件下衰老的一种新的调节因子 和EoE炎症使用一种创新的方法，结合人体内窥镜活检的功能评价， 3D食管类器官和以年龄相关性纤维化为特征的EoE小鼠模型。这些研究有很大的 有可能为食管中的年龄相关机制/细胞表型提供新的见解，并揭示 EoE和其他影响食管的年龄相关疾病的新生物标志物和治疗靶点。

Project Summary Esophageal dysfunction and pathology represent significant health burdens in the United States and worldwide. While patient age is an established risk factor for dysphagia, esophageal cancer and Eosinophilic Esophagitis (EoE)-associated subepithelial fibrosis, our understanding of the biology of aging in the esophagus remains elusive. Under homeostatic conditions, esophageal squamous epithelium comprises a basal compartment of proliferative cells that undergo differentiation in suprabasal layers and luminal desquamation, facilitating tissue renewal. Perturbation of this defined proliferation/differentiation gradient in esophageal epithelium is a feature of esophageal pathologies, including EoE. While the prevalence of BCH is nearly identical in pediatric and adult patients with active EoE, preliminary data indicate that BCH is present in ~20% of normal esophageal epithelial specimens from adults while remaining undetectable in normal pediatric specimens. We have recently demonstrated that autophagy (‘self-eating’) is activated in esophageal epithelium in response to EoE inflammation, serving to limit BCH and eosinophilia. Preliminary data indicate that autophagy flux is stalled in aged esophageal epithelium under normal conditions. Moreover, EoE induction in aged mice results in diminished eosinophilia and subepithelial fibrosis. The overarching hypothesis is that age-associated decline in esophageal epithelial autophagy flux impairs tissue homeostasis and contributes to age-associated alterations in EoE phenotype. To test this hypothesis, we will define the functional relationship between mTORC1/autophagy signaling and age-associated esophageal basal cell hyperplasia (Aim 1); elucidate the functional role of epithelial autophagy in age-associated EoE fibrosis (Aim 2); and investigate the role of epithelial autophagy in the EoE inflammatory response in the context of aging (Am 3). The biology of aging in the esophagus represents a significant knowledge gap as understanding mechanisms of tissue aging has the potential to improve strategies for diagnosis, monitoring and therapy of widely prevalent esophageal diseases, including EoE and cancer. Here, we investigate epithelial autophagy as a novel regulator of aging in the esophagus under conditions of homeostasis and EoE inflammation using an innovative approach coupling functional evaluation of human endoscopic biopsies, 3D esophageal organoids and a murine model of EoE featuring age-associated fibrosis. These studies have great potential to provide novel insight into age-relevant mechanisms/cellular phenotypes in the esophagus and unveil new biomarkers and therapeutic targets for EoE and other age-associated disorders affecting the esophagus.