Investigating the relationship between macrophage ontogeny and function during pancreatitis

项目总结/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、嗜中性粒细胞和T细胞。虽然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力驱动因素。尽管如此，靶向巨噬细胞产生的细胞因子 在治疗上并没有太大的成功。这一点，沿着事实，胰腺炎是一个很好的描述风险 胰腺癌的因素，说明需要建立更好的方法来靶向细胞类型， 疾病进展。虽然巨噬细胞是胰腺炎和胰腺炎的有吸引力的治疗靶点， 在胰腺癌中，迄今为止的研究主要集中在来源于浸润性单核细胞的那些。最近 谱系追踪研究表明，组织内的巨噬细胞不仅来源于单核细胞， 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， 发病机制，包括胰腺癌，胚胎来源的巨噬细胞采取独特的功能，从那些 来源于单核细胞。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变化。然而，目前还不完全清楚是什么机制驱动了 不同来源的巨噬细胞反应不同，以及胚胎来源的巨噬细胞如何影响 肿瘤进展不同于来自单核细胞的那些。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具有不同功能作用 进展首先，我已经证明了胚胎和单核细胞衍生的巨噬细胞都积累了 在胰腺炎时会出现。这里将使用额外的谱系追踪小鼠模型来加强 这一论点，并允许我调查的变化，激活这些人口之间的稳态和 炎症通过CCR 2基因的遗传缺失减少单核细胞衍生的巨噬细胞，涉及 单核细胞运输，不足以抑制胰腺炎期间胰腺中的总巨噬细胞数量， 这些小鼠在疾病进展方面没有表现出差异。以胚胎巨噬细胞亚群为靶点， 进一步帮助我们了解这些细胞的功能作用，并确定其治疗效果。这些 目的不仅有助于扩大我们对巨噬细胞生物学的知识，而且还可以专注于我长期以来的研究。 对免疫学和人类疾病感兴趣。通过本建议获得的培训还将建立在 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，即改善癌症免疫疗法和免疫调节对癌症的影响。 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.