Pro-inflammatory cytokines in hematopoietic stem cell function

造血干细胞功能中的促炎细胞因子

• 批准号: 8768233
• 负责人: Eric M Pietras
• 金额: $ 11.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-25 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768233
• 关键词: Address; Affect; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Bacterial Infections; Bioinformatics; Biology; Biomedical Research; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; California; Cell Adhesion Molecules; Cell Culture Techniques; Cell Cycle; Cell Maintenance; Cell Proliferation; Cell Separation; Cell physiology; Cells; Characteristics; Chronic; Collaborations; Collagen; Complex; Cues; Data; Development; Developmental Process; Disease; Doctor of Philosophy; Environment; Equilibrium; Exposure to; Faculty; Functional disorder; Goals; Granulopoiesis; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Research; Hematopoietic stem cells; Homeostasis; Human; Image; Immune; Immune system; Immunologist; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Institutes; Integrins; Interferon Type I; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Investigation; Laboratories; Link; Los Angeles; Lymphoid; Medicine; Mentors; Mentorship; Microscopy; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Natural regeneration; Organism; Outcome; Pathogen detection; Pathogenesis; Patients; Population; Predisposition; Production; Proliferating; Regulation; Research; Research Personnel; Resolution; Resources; Role; San Francisco; Signal Transduction; Stem Cell Research; Stress; Techniques; Technology; Testing; Time; Tissues; Training; Universities; Work; acute stress; base; cytokine; cytopenia; experience; fitness; hematopoietic stem cell fate; in vivo; insight; mouse model; notch protein; novel therapeutic intervention; oncology; programs; public health relevance; response; self-renewal; single cell analysis; stem cell biology; stem cell differentiation; trafficking

DESCRIPTION (provided by applicant): Candidate: Eric M. Pietras is a postdoctoral scholar who received his Ph.D. at the University of California, Los Angeles (UCLA) for work characterizing intracellular pathogen detection mechanisms and the role of pro- inflammatory cytokines in orchestrating the mobilization of immune cells in response to bacterial infection. His research in the laboratory of Dr. Genhong Cheng identified the pro-inflammatory cytokines interleukin (IL)-1 and interferon (IFN)-gamma as key inducers of myeloid cell recruitment following in vivo bacterial challenge in mice. As a postdoctoral scholar in the laboratory of Dr. Emmanuelle Passegue at the University of California, San Francisco (UCSF), he has continued to investigate the function of these pro-inflammatory cytokines but in the context of normal and leukemic hematopoiesis. Using mouse models of human myeloproliferative neoplasms (MPNs), he showed that MPNs are associated with increased systemic levels of many pro- inflammatory cytokines, and helped demonstrate their key roles in promoting disease pathogenesis by altering the biology of hematopoietic progenitors and cells in the BM niche. He is now focused on understanding the role of type I interferons (IFN-1s) and IL-1 in regulating hematopoietic stem cell (HSC) function and fate choice. The candidate's short-term goal is to continue his mentored studies to develop his independent line of research and obtain further training in bioinformatics, single-cell expression analysis, and single-cell time lapse microscopy, with a long-term goal of understanding how the systemic cytokine milieu affects HSC biology at steady state and during chronic inflammation, as an independent faculty researcher. Environment: The proposed work will take place in the laboratory of Dr. Emmanuelle Passegue, in the Department of Medicine, Division of Hematology/Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, a world-class biomedical research university. The mentor's laboratory is highly respected in the field of HSC biology and has been very productive in using mouse models of human hematological malignancies to study the biology of normal and transformed HSCs. The candidate has access to significant resources at UCSF, including dedicated cell sorting facility and an array of cores for mouse work, microscopy, and cell culture. The candidate will receive guidance and scientific training from Dr. Passegue, and has designated a co-mentor, Dr. Jason Cyster, a highly accomplished immunologist who specializes in the study of systemic immune cell trafficking. He has also established a strong collaboration with Dr. Timm Schroeder at the Swiss Institute of Technology, who developed pioneering single-cell tracking techniques that will be used in the proposed work. He has also assembled a mentorship committee composed of established leaders from UCSF to oversee and enhance his mentored training experience. Research: Hematopoietic stem cells (HSCs) are a rare population of self-renewing bone marrow (BM) cells that generate all mature lineages of blood cell for the lifetime of an organism. HSCs are typically kept in a dormant state, they are capable of rapidly entering the cell cycle and differentiating to produce needed mature progeny in response to infection or injury. While such stresses are associated with the production of a complex array of inflammatory cytokines by mature immune cells and other tissues, the direct effects of these pro- and anti-inflammatory cytokines on the biology of HSCs remain largely unknown. Moreover, the extent to which systemic levels of inflammatory cytokines regulate HSC homeostasis has not been extensively explored. This is particularly true in the context of chronic inflammatory diseases, a range of conditions where elevated levels of pro-inflammatory cytokines may alter HSC self-renewal and differentiation activities, hence leading to the degraded HSC function observed in human patients. Our preliminary data suggest that pro-inflammatory cytokines such as IL-1 and IFN-1s have profound effects on HSC fate choices and alter survival, differentiation and self-renewal activities. Here, we propose to comprehensively investigate the effects of IL-1 and IFN-1s, as well as the anti-inflammatory cytokine IL-10, on HSC function and homeostasis using the mouse as a highly conserved model of hematopoiesis. In Aim 1, we will assess how IL-1, IFN-1s, and IL-10 direct HSC fate choices and affect the molecular networks governing HSC differentiation and self-renewal. In Aim 2, we will address the roles of IL-1, IFN-1s, and IL-10 in regulating steady-state HSC homeostasis and their response to acute stress using Ifnar-/-, Il1r1-/-, and Il10-/- mice. We will also examine how these cytokines affect the interaction between HSCs and their BM niche and their role in governing HSC function. In Aim 3, we will explore how chronic IFN-1- and IL-1-driven inflammation degrades HSC function in vivo. We will assess how exposure to chronic inflammation alters the molecular networks regulating HSC function and whether blockade of pro-inflammatory IFN-1 and IL-1 signaling can revert these deleterious effects and restore HSC fitness and blood production. Taken together, these exciting studies will greatly enhance our understanding of the critical relationship between inflammation and hematopoiesis, and will provide a basis for therapies aimed at restoring normal HSC function in patients suffering from chronic inflammatory diseases.

描述（由申请人提供）：候选人：埃里克M。Pietras是一位博士后学者，他获得了博士学位。在加州大学洛杉矶分校（UCLA），研究了细胞内病原体检测机制和促炎细胞因子在协调免疫细胞动员以应对细菌感染中的作用。他 Genhong Cheng博士实验室的研究确定了促炎细胞因子白细胞介素（IL）-1和干扰素（IFN）-γ是小鼠体内细菌攻击后骨髓细胞募集的关键诱导物。作为加州大学弗朗西斯科分校（UCSF）Emmanuelle Passegue博士实验室的博士后学者，他继续研究这些促炎细胞因子的功能，但在正常和白血病造血的背景下。使用人类骨髓增生性肿瘤（MPN）的小鼠模型，他表明MPN与许多促炎细胞因子的全身水平增加相关，并通过改变BM生态位中造血祖细胞和细胞的生物学来帮助证明它们在促进疾病发病机制中的关键作用。他现在专注于了解I型干扰素（IFN-1 s）和IL-1在调节造血干细胞（HSC）功能和命运选择中的作用。候选人的短期目标是继续他的指导研究，以发展他的独立研究路线，并获得生物信息学，单细胞表达分析和单细胞延时显微镜的进一步培训，长期目标是了解系统性细胞因子环境如何影响HSC生物学在稳态和慢性炎症期间，作为一名独立的教师研究员。工作环境：拟议的工作将在Emmanuelle Passegue博士的实验室进行，该实验室位于UCSF的医学系，血液学/肿瘤学系，Eli和Edythe Broad再生医学和干细胞研究中心，UCSF是世界一流的生物医学研究型大学。导师的实验室在HSC生物学领域备受推崇，并且在使用人类血液恶性肿瘤的小鼠模型研究正常和转化HSC的生物学方面非常富有成效。候选人可以获得UCSF的重要资源，包括专用的细胞分选设施和用于小鼠工作，显微镜和细胞培养的核心阵列。 候选人将接受Passegue博士的指导和科学培训，并指定了一位共同导师Jason Cyster博士，他是一位非常有成就的免疫学家，专门研究系统性免疫细胞贩运。他还与瑞士理工学院的Timm Schroeder博士建立了密切的合作关系，后者开发了将用于拟议工作的开创性单细胞跟踪技术。他还组建了一个由UCSF领导人组成的指导委员会，以监督和加强他的指导培训经验。研究：造血干细胞（HSCs）是一种罕见的自我更新的骨髓（BM）细胞群体，其在生物体的一生中产生所有成熟的血细胞谱系。HSC通常保持在休眠状态，它们能够快速进入细胞周期并响应于感染或损伤而分化以产生所需的成熟后代。虽然这种应激与成熟免疫细胞和其他组织产生一系列复杂的炎性细胞因子有关，但这些促炎和抗炎细胞因子对HSC生物学的直接影响在很大程度上仍然未知。此外，全身水平的炎症细胞因子调节HSC稳态的程度还没有得到广泛的探讨。这在慢性炎性疾病的情况下尤其如此，所述慢性炎性疾病是一系列病症，其中促炎细胞因子水平升高可能改变HSC自我更新和分化活性，因此导致在人类患者中观察到的HSC功能退化。我们的初步数据表明，促炎细胞因子，如IL-1和IFN-1 s对HSC的命运选择有深远的影响，并改变生存，分化和自我更新活动。在这里，我们建议全面调查IL-1和IFN-1 s，以及抗炎细胞因子IL-10，对HSC功能和稳态的影响，使用小鼠作为一个高度保守的造血模型。在目标1中，我们将评估IL-1，IFN-1 s和IL-10如何指导HSC的命运选择，并影响HSC分化和自我更新的分子网络。在目标2中，我们将使用Ifnar-/-，Il 1 r1-/-和Il 10-/-小鼠来说明IL-1，IFN-1 s和IL-10在调节稳态HSC稳态及其对急性应激反应中的作用。我们还将研究这些 细胞因子影响HSC和它们的BM小生境之间的相互作用以及它们在控制HSC功能中的作用。在目标3中，我们将探讨慢性IFN-1和IL-1驱动的炎症如何降低体内HSC功能。我们将评估暴露于慢性炎症如何改变调节HSC功能的分子网络，以及阻断促炎性IFN-1和IL-1信号传导是否可以逆转这些有害作用并恢复HSC适应性和血液生成。总之，这些令人兴奋的研究将大大提高我们对炎症和造血之间关键关系的理解，并将为旨在恢复慢性炎症性疾病患者正常HSC功能的治疗提供基础。