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

这一建议解决炎症和癌症之间的联系，并试图确定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关键作用。虽然HDC作为CKK-¿/胃泌素受体信号下游酸分泌的调节剂已经得到了很好的研究，但Timothy Wang博士的研究小组最近发现了组氨酸脱羧酶（HDC）在早期未成熟髓系细胞（IMCs）中的关键功能，其特征是髓系衍生抑制细胞（MDSCs）和肿瘤相关中性粒细胞（tan）。因此，在上述研究中，HDC将被用作研究这些细胞类型在癌症发生和发展中的作用的标记物。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。人们相信这项工作有可能改变骨髓细胞的模式及其在癌症中的作用。未成熟的骨髓细胞，如MDSCs和TANs，已被证明在人类癌症中积累，并有助于癌症的发展和进展。这些研究将进一步确定HDC作为导致癌症的未成熟髓样细胞的新标记物的效用，以及组胺在可能抑制MDSCs/TANs中的作用。此外，这项工作可能有助于阐明针对IMCs的策略，以预防或治疗胃肠道癌症。提出了以下具体目标，每个目标都针对一个特定的假设：表达hdc的CD11b+Gr1+细胞是产生成熟单核细胞、粒细胞和其他细胞类型的髓系前体吗？hdl缺乏和癌变对脾和骨髓成熟的影响是什么？在致癌刺激过程中表达hdc的IMCs是如何募集的？

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?