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.

摘要 造血干细胞和祖细胞（HSPCs）是一种罕见的自我更新骨髓（BM）群体 能够产生生物体生命周期中所有成熟谱系血细胞的细胞。在成人中，静止的HSPC 存在于低氧骨髓生态位（1- 4%O2生理性低氧）内，并能够迅速进入 细胞周期和分化产生白细胞以应对入侵的病原体。导师的实验室 发现炎症的消退受新介质的空间和时间产生的控制， 阐明了专门的促消退介质（SPM），一个包括脂氧素（LX）的autacoids超家族， resolvins（Rv）、protectins（PD）和maresins（MaR）。SPM生物合成结构和功能 在导师的实验室里建立并得到其他人的证实。SPM是次纳摩尔的有效立体选择性 促进微生物清除和遏制的激动剂，同时通过加速宿主存活来增强宿主存活 解决机制。这项建议是基于正在进行的工作的新发现;我们确定，使用状态- 最先进的代谢脂质组学分析，生理性缺氧条件下HSPC中的特定SPM簇，包括 Resolvin D1（RvD 1）、Resolvin D4（RvD 4）、Resolvin E1（RvE 1）、Maresin 1（MaR 1）和脂氧素B4（LXB 4）。还有， 我们最近在健康人骨髓中鉴定了一种新的SPM，Resolvin E4（RvE 4）。组织经历了 生理性缺氧小生境（如BM）通过未定义的机制具有大量SPM。因此我们 我建议严格检验以下假设：在生理性缺氧中， BM中产生的介质（SPM）对于调节HSPC从头应答和/或 感染的远端部位的侵袭，以及维持BM稳态。以下目标是 通过使用最新技术水平的组学平台（例如，代谢脂质组学（LC-MS/MS），质谱细胞术 在鼠和人HSPC中使用CyTOF（CyTOF）和单细胞RNA测序（sc-RNA-seq），以：1）确定 生理性缺氧对BM生态位（K99）内源性新SPM产生的影响，以及2）建立调节机制 HSPC分化和对SPM簇感染的应答，特别是RvD 1、RvD 4、MaR 1和 新RvE 4（K99/R 00）。K99指导阶段将在布里格姆妇女医院和哈佛进行 在两位国际公认的科学家查尔斯·N.瑟涵 在SPM的结构解析及其功能的领导者和列奥纳多Zon教授，在SPM的结构解析及其功能的领导者， 造血Libreros博士将由一个科学委员会/合作者进一步提供建议， 研究计划的各个方面：Matthew Spite博士、Mark Perrella博士和大卫斯卡登教授。目标 本提案的目的是为申请人提供一个全面的科学和职业发展计划， 所需的技能过渡到一个独立的教师职位（R 00）。这些研究的结果将产生 从根本上对SPM的功能和HSPC生物学中的新的促分解途径有了新的认识。 这些发现可以帮助开发血液疾病的新疗法，并提供基本的治疗方法。 了解骨髓如何支持感染期间的解决方案。