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: 10341129
• 负责人: John M Baer
• 金额: $ 2.76万
• 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 2022-12-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341129
• 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 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.

项目概要/摘要 与胰腺炎相关的炎症引发胰腺内白细胞的积聚。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作用 对于胰腺炎中的每种细胞类型，大多数关注点都集中在巨噬细胞上，因为它们被认为 是炎症细胞因子产生的有效驱动因素。尽管如此，针对巨噬细胞产生的细胞因子 在治疗上尚未取得太大成功。再加上胰腺炎是一种明确描述的风险这一事实 胰腺癌的因素，说明需要建立更好的方法来靶向驱动细胞类型 疾病进展。尽管巨噬细胞是胰腺炎和胰腺炎的一个有吸引力的治疗靶点 胰腺癌，迄今为止的研究主要集中于源自浸润性单核细胞的癌症。最近的 谱系追踪研究表明，组织内的巨噬细胞不仅起源于单核细胞，而且起源于单核细胞。 也来自胎儿发育期间的胚胎祖细胞。此外，已经表明，在某些模型中 包括胰腺癌在内的发病机制，胚胎来源的巨噬细胞采用了这些细胞的独特功能 源自单核细胞。对胰腺癌的研究还表明，胚胎巨噬细胞可能具有独特的 促进肿瘤进展和纤维化改变。然而，目前尚不完全了解是什么机制驱动 不同来源的巨噬细胞的反应不同，以及胚胎来源的巨噬细胞可能如何影响 肿瘤进展与源自单核细胞的肿瘤进展不同。我推测不同的巨噬细胞 起源在胰腺炎和胰腺炎相关的癌前病变中发挥功能上不同的作用 进展。初步地，我已经证明胚胎和单核细胞来源的巨噬细胞都会积累 胰腺炎期间在胰腺中。这里将使用额外的谱系追踪小鼠模型来加强 这个论点并让我研究这些群体在稳态和稳态之间的激活变化 炎。通过 CCR2 基因的遗传删除减少单核细胞衍生的巨噬细胞，参与 单核细胞运输不足以抑制胰腺炎期间胰腺中的巨噬细胞总数， 这些小鼠的疾病进展没有差异。靶向胚胎巨噬细胞亚群可能 进一步帮助我们了解这些细胞的功能作用并确定其治疗功效。这些 目标不仅有助于扩展我们对巨噬细胞生物学的知识，而且还集中于我长期以来的研究 对免疫学和人类疾病感兴趣。通过该提案获得的培训也将建立在 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能够进一步 推动我的职业目标，即改善癌症免疫疗法以及免疫调节对癌症的影响 炎症性疾病。