Esophageal tissue aging under homeostatic and inflammatory conditions

项目摘要 食道功能障碍和病理在美国和世界范围内都是沉重的健康负担。 虽然患者年龄是吞咽困难、食道癌和嗜酸性食管炎的既定危险因素 (EoE)相关的上皮下纤维化，我们对食道衰老生物学的理解仍然存在 难以捉摸。在动态平衡条件下，食道鳞状上皮由一个底部隔室组成。 在基底上层和管腔脱屑中经历分化的增殖细胞，促进组织 更新。这一明确的增殖/分化梯度的扰动是食道上皮的一个特征 食道病理，包括EoE。而BCH在儿童和成人中的患病率几乎相同 活动期EoE患者，初步数据显示BCH存在于约20%的正常食道上皮中 来自成人的标本，而在正常的儿科标本中仍然检测不到。我们最近做了 证明食道上皮对EoE的反应激活了自噬(自噬) 炎症，用于限制BCH和嗜酸性粒细胞增多症。初步数据显示，自噬通量停滞在 正常情况下老化的食道上皮。此外，在老龄小鼠中诱导EoE会导致 减少嗜酸性粒细胞增多和上皮下纤维化。最重要的假设是，随着年龄的增长， 食道上皮细胞自噬通量损害组织内稳态并促进年龄相关性改变 在EoE表型中。为了验证这一假设，我们将定义mTORC1/自噬之间的功能关系 信号与年龄相关的食道基底细胞增生(目标1)；阐明上皮细胞的功能作用 年龄相关性EoE纤维化中的自噬(目标2)；并研究EoE中上皮自噬的作用 衰老背景下的炎症反应(AM 3)。食道衰老的生物学代表了一种 由于对组织衰老机制的理解具有改进策略的潜力，因此显著的知识差距 用于诊断、监测和治疗广泛流行的食道疾病，包括食管炎和癌症。这里, 我们研究了在动态平衡条件下，上皮细胞自噬作为一种新的食道衰老调节因子。 和EoE炎症，使用一种结合人类内窥镜活检功能评估的创新方法， 3D食道器官和以年龄相关纤维化为特征的EoE小鼠模型。这些研究有很大的意义 为年龄相关机制/食道细胞表型提供新的洞察力并揭开面纱 EoE和其他影响食道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.