From stomach tissue to cellular mechanisms: unraveling the role of mononuclear phagocytes in the pathophysiology of gastroparesis

摘要 胃轻瘫是一种以胃排空延迟为特征的慢性胃肠动力障碍。 腹痛、恶心和呕吐。在过去的十年里，它的发病率增加了三倍，而且还在增加 医疗成本增加了10倍。提示免疫失调在高血压的病理生理机制中起一定作用。 然而，免疫细胞机制在很大程度上仍然不清楚，特别是在人类身上。这是 这在很大程度上是因为对人类免疫细胞的类型和功能了解有限 胃。这一认识上的差距是理解细胞机制的一个重大障碍。 对于疾病，以及对新的治疗策略的合理设计。我们使用质量细胞术的初步数据 (CyTOF)显示，人的胃中有更多样化的单核吞噬细胞群体 比之前预想的要好。我们的研究还首次指出，这种疾病不仅影响 如前所述，胃的肌层和胃粘膜也是如此。重要的是，单核细胞 胃瘫患者粘膜吞噬细胞的数量和功能失调，这与 胃排空延迟。基于这些数据，我们的中心假设是胃瘫患者 港湾失调的粘膜和单核巨噬细胞肌层与病理生理学的关系 这种疾病。在三个具体目标中，我们建议解决胃粘膜和 胃瘫患者单核肌层吞噬细胞的分辨率到目前为止还没有做过。 我们还将探讨神经肽在调节胃单核吞噬细胞功能中的作用。 在胃瘫期间。为了实现这些目标，我们将利用允许 以公正的方式鉴定单核巨噬细胞。这些方法将与EX相结合 旨在解开细胞机制的活体功能分析和胃排空小鼠模型 疾病的威胁。我们的理论基础是通过研究人类胃的特性，即表型和功能 单核吞噬细胞，我们可以阐明胃排空延迟的细胞机制 在胃瘫中。这一提议有可能影响治疗策略的合理设计 胃瘫。

ABSTRACT Gastroparesis is a chronic gastrointestinal motility disorder characterized by delayed gastric emptying, chronic abdominal pain, nausea and vomiting. Its incidence has increased 3-fold in the last decade, which has increased healthcare costs by 10-fold. It is suggested that immune dysregulation plays a role in the pathophysiology of the disease; however, the immune cellular mechanisms remain largely unknown, especially in humans. This is largely in part because of limited knowledge on the types and functions of immune cells present in the human stomach. This gap in knowledge presents a significant barrier to understanding the cellular mechanisms of disease, and for the rational design of novel therapeutic strategies. Our preliminary data using mass cytometry (CyTOF) shows that the human stomach harbors mononuclear phagocyte populations that are more diverse than previously appreciated. Our studies also point, for the first time, to a disease that affects not only the stomach muscularis as previously suggested, but also the stomach mucosa. Importantly, mononuclear phagocytes in the mucosa of gastroparesis patients are dysregulated in numbers and function, which correlates with delayed stomach emptying. Based on these data, our central hypothesis is that gastroparesis patients harbor dysregulated mucosa and muscularis mononuclear phagocytes that contribute to the pathophysiology of the disease. In three specific aims, we propose to resolve the identity and dysregulation of stomach mucosa and muscularis mononuclear phagocytes in gastroparesis patients at a resolution that has not been done until now. We will also explore the role of a neuronal peptide in modulating stomach mononuclear phagocyte function during gastroparesis. To achieve these aims, we will take advantage of approaches that allow for the identification of mononuclear phagocytes in an unbiased fashion. These approaches will be combined with ex vivo functional assays and a mouse model of stomach emptying with the goal of unraveling cellular mechanisms of disease. Our rationale is that by investigating the identity, i.e., phenotype and function, of human stomach mononuclear phagocytes, we can elucidate the cellular mechanisms underpinning delayed stomach emptying in gastroparesis. This proposal has the potential to impact the rational design of therapeutic strategies for gastroparesis.