Investigating the relationship between macrophage ontogeny and function during pancreatitis

项目摘要/摘要 与胰腺炎相关的炎症会导致白细胞在胰腺内积聚。族长 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，大部分焦点都集中在巨噬细胞上，正如人们所认为的那样 成为炎性细胞因子产生的有力推动者。尽管如此，靶向巨噬细胞产生的细胞因子 在治疗上并没有看到太多成功。这一点，以及胰腺炎是一种很好地描述的风险的事实 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 疾病的发展。尽管巨噬细胞是胰腺炎和慢性胰腺炎的治疗靶点 胰腺癌，到目前为止，研究主要集中在那些来自浸润性单核细胞的肿瘤。近期 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 也来自胎儿发育过程中的胚胎祖细胞。此外，已经表明，在一些型号的 发病机制，包括胰腺癌，胚胎来源的巨噬细胞具有独特的功能 来源于单核细胞。对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改变。然而，目前还不完全了解是什么机制推动了这一进程 不同来源的巨噬细胞反应不同，以及胚胎来源的巨噬细胞可能如何影响 肿瘤的进展不同于单核细胞的进展。我假设不同的巨噬细胞 起源在胰腺炎和胰腺炎相关癌前病变中的作用不同 进步。我已经初步证明，胚胎和单核细胞来源的巨噬细胞都会积聚 在胰腺炎期间的胰腺中。这里将使用其他血统追踪小鼠模型来加强 这一论点，并使我能够调查这些群体在稳态和 发炎。通过CCR2基因的基因缺失减少单核细胞来源的巨噬细胞，参与 单核细胞运输，不足以在胰腺炎期间抑制胰腺中的巨噬细胞总数， 而这些小鼠在疾病进展方面没有表现出任何差异。以胚胎巨噬细胞亚群为靶点可能 进一步帮助我们了解这些细胞的功能作用，并确定它们的治疗效果。这些 AIMS不仅有助于扩大我们对巨噬细胞生物学的了解，还将专注于我长期以来 对免疫学和人类疾病感兴趣。通过这项提议接受的培训也将建立在 我在免疫学和癌症生物学研究方面的技能。这些宝贵的技能将使我能够进一步 推动我的职业目标，提高癌症免疫疗法和免疫调节的影响 炎症性疾病。

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.