Investigating the relationship between macrophage ontogeny and function during pancreatitis

研究胰腺炎期间巨噬细胞个体发育与功能的关系

• 批准号: 10116955
• 负责人: John M Baer
• 金额: $ 3.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116955
• 关键词: Acceleration; Adopted; Adoptive Transfer; Adult; Automobile Driving; Biology; Bone Marrow; Brain; Cancer Biology; Cells; Clinical; Data; Development; Digestive System Disorders; Disease; Disease Progression; Embryo; Fetal Development; Fetal Liver; Fibrosis; Gene Expression Profile; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Heart; Hematopoietic stem cells; Hospitalization; Immune; Immunology; Inflammation; Inflammatory; Injury; Investigation; Knowledge; Kupffer Cells; Lesion; Leukocytes; Liver; Lung; Malignant neoplasm of pancreas; Mediating; Metaplasia; Microglia; Modeling; Mus; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatitis; Pathogenesis; Pathology; Phenotype; Population; Production; Risk Factors; Role; Shapes; T-Lymphocyte; Technical Expertise; Therapeutic; Tissues; Training; Treatment Efficacy; Work; Yolk Sac; acute pancreatitis; base; cancer immunotherapy; career; cell type; cellular targeting; cytokine; experimental study; fetal; gastrointestinal; human disease; immunoregulation; improved; interest; macrophage; monocyte; mouse model; neutrophil; pancreas development; pancreatic neoplasm; pancreatic tumorigenesis; premalignant; progenitor; skills; success; targeted treatment; therapeutic cytokines; therapeutic target; trafficking; training opportunity; tumor; tumor initiation; tumor progression; tumorigenesis

Project Summary/Abstract Inflammation associated with pancreatitis initiates accumulation of leukocytes within the pancreas. Chief among these cells are macrophages, neutrophils, and T cells. Although studies have identified important roles for each of these cell types in pancreatitis, most of the focus has been on macrophages, as they are thought to be potent drivers of inflammatory cytokine production. Despite this, targeting macrophage-produced cytokines has not seen much success therapeutically. This, along with the fact that pancreatitis is a well described risk factor for pancreatic cancer, illustrates the need for establishing better ways to target the cell types driving disease progression. Although macrophages are an attractive therapeutic target in both pancreatitis and pancreatic cancer, study thus far has primarily focused on those derived from infiltrating monocytes. Recent lineage-tracing studies have shown that macrophages within tissues originate not only from monocytes, but also from embryonic progenitors during fetal development. Further, it has been shown that in some models of pathogenesis, including pancreatic cancer, embryonic-derived macrophages adopt unique functions from those derived from monocytes. Study of pancreatic cancer also revealed that embryonic macrophages may uniquely promote tumor progression and changes in fibrosis. However, it is not fully understood what mechanisms drive macrophages of different origin to react differently, and how embryonic-derived macrophages might impact tumor progression differently than those derived from monocytes. I hypothesize that macrophages of different origin adopt functionally distinct roles in both pancreatitis and pancreatitis-associated pre-malignant progression. Preliminarily, I have shown that both embryonic and monocyte-derived macrophages accumulate in the pancreas during pancreatitis. Additional lineage-tracing mouse models will be used here to strengthen this argument and allow me to investigate changes in activation of these populations between steady-state and inflammation. Reducing monocyte-derived macrophages by genetic deletion of the CCR2 gene, involved in monocyte trafficking, is not sufficient to restrain total macrophage numbers in the pancreas during pancreatitis, and these mice show no difference in disease progression. Targeting the embryonic macrophage subset may further help us understand the functional role of these cells and determine their therapeutic efficacy. These aims will not only help expand our knowledge of macrophage biology, but also focus on my long-standing interests in immunology and human disease. The training received through this proposal will also build upon my technical skills in immunology and study of cancer biology. These invaluable skills will allow me to further push towards my career goals of improving cancer immunotherapies and impact of immune modulation on inflammatory disorders.

项目摘要/摘要 与胰腺炎相关的炎症会引起白细胞在胰腺内的积累。首席 这些细胞包括巨噬细胞，中性粒细胞和T细胞。尽管研究已经确定了重要的作用 对于胰腺炎中的每种细胞类型，大多数重点都放在巨噬细胞上，因为它们被认为是 成为炎性细胞因子产生的有效驱动因素。尽管如此，靶向巨噬细胞产生的细胞因子 没有在治疗上看到太多成功。这是胰腺炎是一个很好的风险 胰腺癌的因素说明了建立更好的靶向细胞类型的方法的必要性 疾病进展。尽管巨噬细胞在胰腺炎和 迄今为止，胰腺癌主要集中在浸润单核细胞中的胰腺癌。最近的 谱系追踪研究表明，组织中的巨噬细胞不仅来自单核细胞，而且源自 同样来自胎儿发育过程中的胚胎祖细胞。此外，已经表明，在某些模型中 发病机理，包括胰腺癌，胚胎来源的巨噬细胞采用独特的功能 源自单核细胞。胰腺癌的研究还表明，胚胎巨噬细胞可能是唯一的 促进肿瘤进展和纤维化的变化。但是，尚不完全了解哪些机制驱动 不同来源的巨噬细胞以不同的反应，以及胚胎衍生的巨噬细胞如何影响 肿瘤的进展不同于单核细胞的肿瘤进展。我假设不同的巨噬细胞 来源在胰腺炎和胰腺炎相关前恶性中采用功能截然不同的作用 进展。我已经表明，胚胎和单核细胞衍生的巨噬细胞都积累 在胰腺炎期间的胰腺。这里将使用其他谱系追踪鼠标模型来加强 这个论点，允许我调查稳态和稳态和 炎。通过涉及CCR2基因的遗传缺失来减少单核细胞衍生的巨噬细胞 单核细胞运输不足以限制胰腺炎期间胰腺的总巨噬细胞数量， 这些小鼠在疾病进展方面没有差异。靶向胚胎巨噬细胞子集可能 进一步帮助我们了解这些细胞的功能作用，并确定它们的治疗功效。这些 目标不仅有助于扩大我们对巨噬细胞生物学的了解，而且还专注于我的长期存在 对免疫学和人类疾病的兴趣。通过此提案获得的培训也将基于 我在免疫学和癌症生物学研究方面的技术技能。这些宝贵的技能将使我进一步 朝着改善癌症免疫疗法和免疫调节影响的职业目标迈向我的职业目标 炎症性疾病。