METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION

描述（由申请人提供）：巨噬细胞具有重要的免疫和局部组织稳态作用，并且改变的巨噬细胞功能被怀疑有助于许多疾病过程，包括动脉粥样硬化、代谢综合征和癌症。巨噬细胞以几种特殊形式（亚群）存在，具有不同的解剖位置，细胞表面标记和功能。虽然循环单核细胞被认为产生这些组织特异性巨噬细胞亚群，但这种组织特异性分化的发育基础尚不清楚。Kenneth Murphy博士实验室先前发表的工作首次证明了特定巨噬细胞亚群（脾红髓巨噬细胞，RPM）发育需要特定转录因子（SpiC）。RPM的主要稳态功能是降解血红素并回收铁用于随后的红细胞生成。候选人在Murphy博士实验室的工作重点是了解SpiC在RPM中的调节和功能。令人惊讶的是，这项工作已经发现，SpiC的表达是由红细胞降解的代谢产物血红素诱导的。进一步的研究揭示了转录抑制因子Bach 1在血红素介导的SpiC调控中的作用。这些发现证明了组织特异性代谢物在指导巨噬细胞多样性中的作用。本项目的目标是表征血红素介导的SpiC诱导的机制，揭示RPM生物学中SpiC控制的发育程序，并研究血红素介导的SpiC诱导的生理和病理意义。Kenneth Murphy博士最近在巨噬细胞和树突状细胞发育和功能领域做出了重大贡献。候选人是一名MD/PhD，已完成临床病理学的住院医师培训，并希望在基础科学方面进一步培训。候选人的长期目标是建立一个独立的研究实验室，研究巨噬细胞在疾病过程中的作用。

DESCRIPTION (provided by applicant): Macrophages have important immune as well as local tissue homeostatic roles, and altered macrophage function is suspected to contribute towards many disease processes including atherosclerosis, metabolic syndrome, and cancer. Macrophages exist in several specialized forms (subsets) that have distinct anatomic locations, cell surface markers, and functions. While circulating monocytes are thought to give rise to these tissue-specific macrophage subsets, the developmental basis for such tissue-specific differentiation is unknown. Previous published work from Dr. Kenneth Murphy's laboratory demonstrated for the first time the requirement for a specific transcription factor (SpiC) for the development of a specific macrophage subset (splenic Red Pulp Macrophage, RPM). The primary homeostatic function of RPMs is to degrade heme and recycle the iron for subsequent erythropoesis. The candidate's work in Dr. Murphy's lab has focused on understanding the regulation and function of SpiC in RPMs. Surprisingly, this work has discovered that SpiC expression is induced by a metabolite of erythrocyte degradation, heme. Further studies uncovered a role for the transcriptional repressor Bach1 in heme mediated regulation of SpiC. These findings demonstrate a role of tissue-specific metabolites in directing macrophage diversity. The goals of this project are to characterize the mechanisms underlying heme-mediated induction of SpiC, uncover the developmental program controlled by SpiC in RPM biology, and investigate the physiological and pathological implications of heme-mediated induction of SpiC. The work proposed here will be carried out in the laboratory of Dr. Kenneth Murphy, who has recently made significant contributions to the area of macrophage and dendritic cell development and function. The candidate is a MD/PhD who has completed residency training in Clinical Pathology and wishes to train further in basic sciences. The long term goal of the candidate is to establish an independent research laboratory investigating the role of macrophages in disease processes.