Bone Marrow Functions of Novel Pro-Resolving Mediators

新型亲解决介质的骨髓功能

• 批准号: 10852343
• 负责人: Stephania Libreros
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852343
• 关键词: Acceleration; Acute; Adult; Agonist; Anabolism; Applications Grants; Autacoids; Blood Cells; Bone Marrow; Bone Marrow Cells; CD14 gene; CD34 gene; CD59 Antigen; Cell Cycle; Cell Differentiation process; Cell Separation; Cells; Cellular biology; Coin; Collaborations; Colony-Forming Units Assay; Containment; Cytometry; Development Plans; Disease; Distal; Environment; Enzymes; Escherichia coli; Essential Fatty Acids; Faculty; Future; Genomics; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Hospitals; Host Defense; Host Defense Mechanism; Human; Hypoxia; Immune; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Institution; International; Invaded; Laboratories; Laboratory Research; Leukocytes; Leukotrienes; Lipids; Lipoxins; Lipoxygenase; Liquid Chromatography; Longevity; Macrophage; Maps; Mass Spectrum Analysis; Measures; Mediator; Mentors; Mentorship; Molecular; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Organ; Organism; Oxygen; Pathologic; Pathway interactions; Peritoneal; Phagocytes; Phase; Phenotype; Physiological; Population; Positioning Attribute; Production; Proliferating; Prostaglandins; Regulation; Research Proposals; Resolution; Role; Scientist; Side; Signal Transduction; Site; Structure; Technology; Testing; Time; Tissues; Transplantation; United States National Institutes of Health; Whole Blood; Woman; career development; clinically relevant; experience; granulocyte; improved; in vivo; insight; lipid mediator; lipoxin B4; medical schools; metabolomics; microbial; monocyte; nanomolar; neutrophil; novel; novel therapeutic intervention; pathogen; peripheral blood; pre-clinical; pressure; prevent; professor; progenitor; programs; response; self-renewal; single cell technology; single-cell RNA sequencing; skills; stem cell function; stem cell proliferation; tandem mass spectrometry; transcriptome sequencing

Abstract Hematopoietic stem cells and progenitors (HSPCs) are a rare population of self-renewing bone marrow (BM) cells that can generate all mature lineage blood cells for the lifespan of an organism. In adults, quiescent HSPCs reside within a hypoxic bone marrow niche (1-4% O2 physiologic hypoxia) and are capable of rapidly entering the cell cycle and differentiate to produce leukocytes in response to an invading pathogen. The mentor’s lab uncovered that resolution of inflammation is governed by spatial and temporal production of novel mediators and elucidated the specialized pro-resolving mediators (SPMs), a superfamily of autacoids that includes lipoxins (LX), resolvins (Rv), protectins (PD), and maresins (MaR). SPM biosynthesis structures and functions were established in the mentor’s lab and confirmed by others. SPMs are sub-nanomolar potent, stereoselective agonists that promote microbial clearance and containment, while enhancing host survival by accelerating host resolution mechanisms. This proposal is based on new findings from work in progress; we identified, using state- of-the-art metabololipidomics profiling, a specific SPM cluster in HSPC under physiologic hypoxia, which includes Resolvin D1 (RvD1), Resolvin D4 (RvD4), Resolvin E1 (RvE1), Maresin 1 (MaR1) and Lipoxin B4 (LXB4). Also, we recently identified a new SPM, Resolvin E4 (RvE4), in healthy human bone marrow. Tissues that experience physiologic hypoxic niches, such as BM, have high amounts of SPMs through undefined mechanisms. Thus, we propose to rigorously test the following hypothesis: In physiologic hypoxia, specialized pro-resolving mediators (SPMs) produced in BM are essential for regulating HSPC responses de novo and/or during infection at distal sites of invasion, as well as maintaining BM homeostasis. The following aims are proposed by using state-of-the-art omics platforms e.g., metabolipidomics (LC-MS/MS), mass cytometry (CyTOF) and single cell RNA sequencing (sc-RNA-seq) in murine and human HSPCs to: 1) determine the impact of physiologic hypoxia on endogenous novel SPM production in BM niche (K99), and 2) establish the regulation of HSPC differentiation and responses to infection by the SPM cluster, specifically RvD1, RvD4, MaR1 and the novel RvE4 (K99/R00). The K99 mentored phase will take place at Brigham and Women’s Hospital and Harvard Medical School under the mentorship of two internationally recognized scientists, Professor Charles N. Serhan, the leader in the structural elucidation of SPMs and their functions and Professor Leonardo Zon, the leader on hematopoiesis. Dr. Libreros will be further advised by a scientific committee/collaborator covering different aspects of the research proposal: Dr. Matthew Spite, Dr. Mark Perrella, and Professor David Scadden. The goal of this proposal is to provide a comprehensive scientific and career development plan for the applicant with the required skills to transition to an independent faculty position (R00). Results from these studies will yield fundamentally new insights into the functions of SPMs and novel pro-resolving pathways in HSPC biology. These discoveries can help develop novel treatments for hematological disorders and provide a basic understanding of how bone marrow supports resolution programs during infections.

抽象的 造血干细胞和祖细胞（HSPC）是罕见的自我更新骨髓（BM） 可以在组织的使用寿命中生成所有成熟血统的细胞。在成年人中，静止的HSPC 居住在缺氧的骨髓生态位（1-4％O2生理缺氧）中，能够快速进入 细胞周期和分化以响应入侵病原体而产生白细胞。导师实验室 发现炎症的分辨率受新型调解者的空间和临时产生的控制 阐明了专业的促分解介体（SPMS），这是一种包括脂毒素（LX）， Resolvins（RV），Protectins（PD）和Maresins（Mar）。 SPM生物合成结构和功能是 在心理实验室中建立，并由其他人确认。 SPM是亚纳摩尔有效的立体选择性 促进微生物清除和遏制的激动剂，同时通过加速宿主来增强宿主生存 解决机制。该提案基于正在进行的工作中的新发现。我们使用状态确定了 ART代谢脂肪组学分析，这是HSPC中的特定SPM簇，包括生理缺氧，其中包括 Resolvin D1（RVD1），Resolvin D4（RVD4），Resolvin E1（RVE1），Maresin 1（MAR1）和Lipoxin B4（LXB4）。还， 我们最近在健康的人骨髓中确定了新的SPM Resolvin E4（RVE4）。经历的组织 通过未定义的机制，生理性低氧壁ni（例如BM）具有大量的SPM。那，我们 严格检验以下假设的建议：在生理缺氧中 BM中产生的介体（SPM）对于确定从头和/或期间的HSPC响应至关重要 在入侵的盘中感染以及维持BM稳态。以下目标是 通过使用最先进的OMICS平台，例如代谢脂肪组学（LC-MS/MS），质量细胞术 鼠和人类HSPC中的（Cytof）和单细胞RNA测序（SC-RNA-SEQ）至：1）确定影响 在BM利基（K99）中内源性新型SPM产生的生理缺氧（K99）和2）建立调节 SPM簇的HSPC分化和对感染的反应，特别是RVD1，RVD4，MAR1和 小说RVE4（K99/R00）。 K99修订阶段将在Brigham和妇女医院和哈佛大学举行 医学院在两位国际认可的科学家查尔斯·塞尔汉教授的心态下， SPM及其功能结构阐明的领导者以及Leonardo Zon教授 造血。科学委员会/合作者将进一步建议Libreros博士 研究建议的各个方面：Matthew Spite博士，Mark Perrella博士和David Scadden教授。目标 该建议的是为申请人提供全面的科学和职业发展计划 过渡到独立教师职位（R00）所需的技能。这些研究的结果将产生 从根本上讲，新的见解SPM的功能和HSPC生物学中新型的促分解途径。 这些发现可以帮助开发有关血液学疾病的新型治疗方法，并提供基本的疗法 了解骨髓如何支持感染过程中的解决方案。