Normal development of myeloid cells and the role of immature myeloid cells in chronic inflammation and carcinogenesis of the colorectal carcinoma

髓系细胞的正常发育及未成熟髓系细胞在结直肠癌慢性炎症和癌变中的作用

• 批准号: 218451922
• 负责人: Privatdozent Dr. Bernhard Renz
• 金额: --
• 依托单位: Division of Digestive and Liver Diseases
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218451922?language=en
• 关键词: Normal; development; myeloid; cells; role

This proposal addresses the link between inflammation and cancer and seeks to define the role of myeloid progenitors in cancer. The enzyme histidine decarboxylase (HDC), which catalyzes the conversion of L-histidine to histamine, plays a key role in the regulation of numerous physiologic processes. While HDC has now been well studied as a regulator of acid secretion downstream of CKK-¿/gastrin receptor signalling, the group of Timothy Wang, MD has recently identified a critical function of histidine decaboxylase (HDC) in early immature myeloid cells (IMCs) that characterizes both myeloid derived suppressor cells (MDSCs) and tumor associated neutrophils (TANs). Thus, in the described studies, HDC will be used as a marker to investigate the role of these cell types in cancer initiation and progression. They have also identified a key role for histamine in differentiation and maturation of myeloid cells and thus there is a potential target for modulating cancer risk. It is believed that this work has the potential to alter the paradigm for myeloid cells and their role in cancer. Immature myeloid cells, such as MDSCs and TANs, have been shown to accumulate in human cancers and contribute to the development and progression of cancer. The proposed studies will define further the utility of HDC as a novel marker for immature myeloid cells that contribute to cancer and the role of histamine in possibly suppressing MDSCs/TANs. In addition, the work may help elucidate strategies for targeting IMCs in order to prevent or treat gastrointestinal cancers.The following specific aims are proposed, each of which addresses a specific hypothesis:1. Are HDC-expressing CD11b+Gr1+ cells myeloid precursors that give rise to mature monocytes and granulocytes and other cell types?2. What is the effect of HDC-deficiency and carcinogenesis on spleen vs. bone marrow maturation?3. How are HDC-expressing IMCs recruited during carcinogenic stimuli?

该提案解决了炎症和癌症之间的联系，并试图定义髓系祖细胞在癌症中的作用。组氨酸脱羧酶（HDC）催化L-组氨酸转化为组胺，在许多生理过程的调节中起着关键作用。虽然HDC现在已被充分研究为CKK-β/胃泌素受体信号传导下游的酸分泌调节剂，但Timothy Wang，MD的小组最近鉴定了组氨酸脱羧酶（HDC）在早期未成熟髓样细胞（IMC）中的关键功能，其表征髓源性抑制细胞（MDSC）和肿瘤相关中性粒细胞（TAN）。因此，在所描述的研究中，HDC将用作标记物以研究这些细胞类型在癌症起始和进展中的作用。他们还确定了组胺在骨髓细胞分化和成熟中的关键作用，因此存在调节癌症风险的潜在靶点。据信，这项工作有可能改变骨髓细胞的范式及其在癌症中的作用。未成熟的骨髓细胞，如MDSC和TAN，已被证明在人类癌症中积累，并有助于癌症的发展和进展。拟议的研究将进一步确定HDC作为导致癌症的未成熟骨髓细胞的新标记物的效用以及组胺在可能抑制MDSC/TAN中的作用。此外，这项工作可能有助于阐明靶向IMC的策略，以预防或治疗胃肠道癌症。 表达HDC的CD 11b + Gr 1+细胞是否为髓样前体细胞，可产生成熟的单核细胞和粒细胞以及其他细胞类型？2. HDC缺乏和癌变对脾脏和骨髓成熟的影响是什么？3. 在致癌刺激过程中，表达HDC的IMC是如何被招募的？