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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要