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

摘要 胃轻瘫是一种慢性胃肠动力障碍，其特征在于胃排空延迟，慢性 腹痛恶心呕吐在过去十年中，其发病率增加了3倍， 医疗保健费用增加10倍。提示免疫调节异常在慢性阻塞性肺疾病的病理生理学中起一定作用。 然而，免疫细胞机制在很大程度上仍然未知，特别是在人类中。这是 这主要部分是因为对存在于人体内的免疫细胞的类型和功能的了解有限， 胃这种知识上的差距对理解细胞内的细胞机制构成了重大障碍。 疾病，并合理设计新的治疗策略。我们使用质谱细胞仪的初步数据 （CyTOF）显示，人类胃中的单核吞噬细胞群体更加多样化， 比以前欣赏。我们的研究还首次指出，一种疾病不仅影响 如前所述的胃肌层，但也包括胃粘膜。重要的是，单核细胞 胃轻瘫患者粘膜中的吞噬细胞在数量和功能上失调， 胃排空延迟基于这些数据，我们的中心假设是胃轻瘫患者 藏失调的粘膜和肌层单核吞噬细胞，有助于病理生理学 这种疾病在三个具体目标中，我们建议解决胃粘膜的身份和失调， 胃轻瘫患者的肌层单核吞噬细胞的解决方案迄今为止尚未完成。 我们也将探讨神经肽在调节胃单核吞噬细胞功能中的作用 在胃轻瘫期间。为了实现这些目标，我们将利用各种方法， 以无偏的方式鉴定单核吞噬细胞。这些方法将与前 体内功能测定和胃排空的小鼠模型，目的是阐明细胞机制 疾病。我们的理由是，通过调查身份，即，人胃的表型和功能 单核吞噬细胞，我们可以阐明胃排空延迟的细胞机制 在胃轻瘫中。这一建议有可能影响治疗策略的合理设计， 胃轻瘫

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.