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

从胃组织到细胞机制：揭示单核吞噬细胞在胃轻瘫病理生理学中的作用

• 批准号: 10493407
• 负责人: Juliana Idoyaga
• 金额: $ 39.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493407
• 关键词: Affect; Biological Assay; Calcitonin Gene-Related Peptide; Cells; Chronic; Clinical Research; Cytometry; Data; Dendritic Cells; Diabetic mouse; Dimensions; Disease; Enteric Nervous System; Environment; Functional disorder; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Goals; Health Care Costs; Healthcare Systems; Human; Immune; Immune response; Incidence; Inflammatory; Interstitial Cell of Cajal; Intestines; Knowledge; Microscopy; Modeling; Mononuclear; Mucous Membrane; Mus; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Nausea and Vomiting; Neurons; Neuropeptides; Organ; Pathway interactions; Patients; Peptide Signal Sequences; Peptides; Phagocytes; Phenotype; Play; Population; Production; Proxy; Research; Resolution; Role; Sampling; Stomach; Testing; Therapeutic; Thick; Time; Tissues; base; cell motility; chronic abdominal pain; cytokine; dimensional analysis; high dimensionality; immune function; immunoregulation; macrophage; monocyte; motility disorder; mouse model; novel; novel therapeutic intervention; rational design; reduce symptoms; stomach motility; targeted treatment

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.

抽象的 胃轻瘫是一种慢性胃肠动力障碍，其特征是胃排空延迟、慢性 腹痛、恶心和呕吐。近十年来其发病率增加了 3 倍 医疗费用增加10倍。这表明免疫失调在疾病的病理生理学中发挥作用。 疾病;然而，免疫细胞机制仍然很大程度上未知，特别是在人类中。这是 很大程度上是因为对人体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。我们使用质谱流式细胞仪获得的初步数据 （CyTOF）表明，人胃中含有更加多样化的单核吞噬细胞群 比以前赞赏的。我们的研究还首次指出，一种疾病不仅影响 如前所述，胃肌层，还有胃粘膜。重要的是，单核 胃轻瘫患者粘膜中的吞噬细胞在数量和功能上失调，这与 胃排空延迟。根据这些数据，我们的中心假设是胃轻瘫患者 粘膜和肌层单核吞噬细胞失调，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和胃黏膜的身份和失调问题。 胃轻瘫患者的肌层单核吞噬细胞的分辨率迄今为止尚未完成。 我们还将探讨神经元肽在调节胃单核吞噬细胞功能中的作用 胃轻瘫期间。为了实现这些目标，我们将利用允许 以公正的方式识别单核吞噬细胞。这些方法将与前 体内功能测定和小鼠胃排空模型，旨在阐明细胞机制 的疾病。我们的理由是，通过研究人类胃的身份，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 在胃轻瘫中。该提案有可能影响治疗策略的合理设计 胃轻瘫。