Bone Marrow Functions of Novel Pro-Resolving Mediators

新型亲解决介质的骨髓功能

基本信息

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
项目类别：
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

项目摘要

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) 是一种罕见的自我更新骨髓 (BM) 群体能够在生物体的整个生命周期中产生所有成熟谱系血细胞的细胞。存在于缺氧的骨髓生态位（1-4% O2 生理性缺氧）内，并且能够快速进入细胞周期并分化产生白细胞以应对入侵的病原体。发现炎症的消退是由新介质的空间和时间产生控制的阐明了专门的促解决介质（SPM），这是一个自体激素超家族，其中包括脂氧素（LX）， resolvins (Rv)、protectins (PD) 和 maresins (MaR) 的生物合成结构和功能。在导师的实验室中建立并得到其他人证实的 SPM 具有亚纳摩尔的强效、立体选择性。促进微生物清除和遏制的激动剂，同时通过加速宿主的存活来增强宿主的生存该提案基于我们使用状态确定的新发现；最先进的代谢脂质组学分析，生理缺氧下 HSPC 中的特定 SPM 簇，其中包括 Resolvin D1 (RvD1)、Resolvin D4 (RvD4)、Resolvin E1 (RvE1)、Maresin 1 (MaR1) 和脂氧素 B4 (LXB4)。我们最近在健康的人类骨髓组织中发现了一种新的 SPM，Resolvin E4 (RvE4)。生理性缺氧环境，例如 BM，通过未明确的机制具有大量 SPM。建议严格检验以下假设：在生理性缺氧中，专门的促解决 BM 中产生的介质 (SPM) 对于从头调节 HSPC 反应和/或在远端侵袭部位的感染以及维持 BM 稳态的目标如下。通过使用最先进的组学平台提出，例如代谢脂组学 (LC-MS/MS)、质谱流式分析 (CyTOF) 和单细胞 RNA 测序 (sc-RNA-seq) 对小鼠和人类 HSPC 进行：1) 确定影响生理性缺氧对 BM 生态位 (K99) 内源性新型 SPM 产生的影响，以及 2) 建立调节 HSPC 分化和对 SPM 簇感染的反应，特别是 RvD1、RvD4、MaR1 和小说 RvE4 (K99/R00) K9 指导阶段将在布莱根妇女医院和哈佛大学进行。医学院在两位国际知名科学家 Charles N. Serhan 教授的指导下， SPM 结构阐明及其功能的领导者和 Leonardo Zon 教授 Libreros 博士将得到涵盖不同领域的科学委员会/合作者的进一步建议。研究提案的方面：Matthew Spite 博士、Mark Perrella 博士和 David Scadden 教授目标。该提案的目的是为申请人提供全面的科学和职业发展计划这些研究的结果将产生过渡到独立教职职位所需的技能（R00）。对 SPM 功能和 HSPC 生物学中新的促解析途径有了全新的认识。这些发现有助于开发血液疾病的新疗法，并提供基础了解骨髓如何支持感染期间的解决方案。