METABOLIC CONTROL OF TISSUE SPECIFIC MACROPHAGE DIFFERENTIATION

组织特异性巨噬细胞分化的代谢控制

• 批准号: 9303241
• 负责人: Malay Haldar
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303241
• 关键词: Address; Anatomy; Anemia; Area; Atherosclerosis; BACH1 gene; BACH2 gene; Back; Basic Science; Biological; Biological Process; Biology; Blood Circulation; Bone Development; Bone Marrow; Cell surface; Clinical Pathology; Dendritic Cells; Development; Disease; Doctor of Philosophy; Erythrocytes; Gene Expression Profiling; Genetic; Goals; Grant; Hematoma; Heme; Hemoglobin; Homeostasis; Immune; Innate Immune System; Iron; Laboratories; Laboratory Research; Location; Malignant Neoplasms; Mediating; Metabolic Control; Metabolic syndrome; Metabolism; Pathologic; Pathway interactions; Physiological; Play; Population; Process; Publishing; Recycling; Regulation; Reporting; Research; Residencies; Resolution; Role; Source; Splenic Red Pulp; Time; Tissues; Training; Transcription Repressor/Corepressor; Work; base; career development; cell type; in vivo; macrophage; monocyte; novel; programs; public health relevance; transcription factor

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.

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角色，并且怀疑巨噬细胞功能改变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。巨噬细胞以几种具有不同解剖位置，细胞表面标记和功能的特殊形式（子集）存在。虽然循环单核细胞被认为会引起这些组织特异性的巨噬细胞子集，但这种组织特异性分化的发育基础尚不清楚。肯尼斯·墨菲（Kenneth Murphy）博士的实验室的先前发表的工作首次证明了特定转录因子（SPIC）的需求，以开发特定的巨噬细胞亚群（脾脏红浆巨噬细胞，rpm）。 RPM的主要体内稳态功能是降解血红素并回收铁以进行红细胞次。候选人在墨菲博士实验室的工作致力于了解SPIC在RPM中的调节和功能。令人惊讶的是，这项工作发现SPIC表达是由红细胞降解的代谢产物诱导的。进一步的研究发现了转录阻遏物Bach1在血红素介导的SPIC调节中的作用。这些发现证明了组织特异性代谢产物在指导巨噬细胞多样性中的作用。该项目的目标是表征血红素介导的SPIC的基础机制，揭示由SPIC在RPM生物学中控制的发育程序，并研究血红素介导的SPIC的生理和病理学意义。这里提出的工作将在肯尼斯·墨菲（Kenneth Murphy）博士的实验室中进行，后者最近为巨噬细胞和树突状细胞发育和功能做出了重大贡献。候选人是医学博士/博士学位，他已经完成了临床病理学的居住培训，并希望在基础科学中进一步培训。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。

项目成果

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality.

• DOI: 10.1016/j.celrep.2021.108917
• 发表时间: 2021-03-30
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Dang, Mai T.;Gonzalez, Michael, V;Gaonkar, Krutika S.;Rathi, Komal S.;Young, Patricia;Arif, Sherjeel;Zhai, Li;Alam, Zahidul;Devalaraja, Samir;To, Tsun Ki Jerrick;Folkert, Ian W.;Raman, Pichai;Rokita, Jo Lynne;Martinez, Daniel;Taroni, Jaclyn N.;Shapiro, Joshua A.;Greene, Casey S.;Savonen, Candace;Mafra, Fernanda;Hakonarson, Hakon;Curran, Tom;Haldar, Malay
• 通讯作者: Haldar, Malay

The Heme Connection: Linking Erythrocytes and Macrophage Biology.

• DOI: 10.3389/fimmu.2017.00033
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Alam MZ;Devalaraja S;Haldar M
• 通讯作者: Haldar M