Inflammatory Regulation of Hematopoietic Stem and Progenitor Cells to Enhance Innate Immunity

造血干细胞和祖细胞的炎症调节以增强先天免疫

• 批准号: 9383703
• 负责人: Katherine Yudeh King
• 金额: $ 42.83万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383703
• 关键词: Acute; Adverse effects; Animals; Aplastic Anemia; Bacterial Infections; Bar Codes; Biochemical; Blood Circulation; Bone Marrow; Bone Marrow Stem Cell; CRISPR/Cas technology; Cancer Patient; Cell Differentiation process; Cell Therapy; Cell division; Cell physiology; Cells; Cessation of life; Co-Immunoprecipitations; Code; Communicable Diseases; Critical Pathways; Data; Ensure; Fever; Frequencies; Functional disorder; Future; Gene Activation; Genes; Genetic Screening; Genetic Transcription; Goals; Granulocyte Colony-Stimulating Factor; Granulopoiesis; Health; Hematopoietic stem cells; Hospitalization; Human; IFNGR1 gene; Immune; Immune response; Immune system; Immunity; Infection; Inflammation; Inflammatory; Infusion procedures; Innate Immune Response; Interferon Type II; Kinetics; Leukocytes; Measures; Mediating; Mediator of activation protein; Methods; Molecular; Multipotent Stem Cells; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; Myositis; Natural Immunity; Neutropenia; Neutropenic Fever; Opportunistic Infections; Outcome; Pancytopenia; Pathogenesis; Patients; Peripheral; Population; Production; RNA Splicing; Recovery; Regulation; Reporter; Research; Role; Sepsis; Signal Pathway; Signal Transduction; Sleeping Beauty; Source; Stem cells; Stimulus; Stress; Testing; Variant; Work; base; bone marrow failure syndrome; cell type; chemotherapy; cytokine; design; granulocyte; high risk; improved; innovation; insight; loss of function; mortality; mouse model; multipotent cell; neutrophil; novel; novel strategies; pathogen; prevent; progenitor; receptor expression; self renewing cell; self-renewal; statistics; success; therapeutic evaluation; therapy development; transcriptome sequencing

Project Summary / Abstract Neutropenia, a deficiency in certain white blood cells, is a common side effect of chemotherapy that exposes patients to a high risk of death from opportunistic infections. Existing methods to restore neutrophils, including G-CSF administration and granulocyte infusions, have not produced a clear improvement in outcome, and new approaches are needed. White blood cells are the product of bone marrow hematopoietic stem and progenitor cells (HSPCs) that can be triggered to divide and differentiate by circulating inflammatory signals. Our prior work shows that the inflammatory cytokine interferon gamma (IFNg) is a potent stimulus for hematopoietic stem cell (HSC) division and myeloid differentiation. Yet persistent IFNg exposure inhibits HSC self-renewal, eventually leading to bone marrow failure. Whether HSCs or their progeny, the multipotent progenitors (MPPs), are equally responsive to IFNg is unknown. Furthermore, a lack of molecular understanding of signaling pathways induced by IFNg to promote HSPC differentiation poses a barrier to utilizing proimmune functions of IFNg while preventing deleterious effects. In preliminary work we identify genes induced in HSCs upon IFNg stimulation, and we show by gain- and loss-of-function studies that an exemplary gene can critically regulate HSPC differentiation. Thus we hypothesize that IFNg-induced transcriptional changes can be used to activate quiescent HSCs to produce more neutrophils, resulting in improved recovery from infection. The rationale is that regulated induction of specific IFNg targets in HSCs may enhance short-term myelopoiesis without disrupting long-term bone marrow function. Three aims are designed to characterize the kinetics, mechanism, and outcome of IFNg-dependent HSPC differentiation. In Aim 1, we will measure the contribution of HSCs versus MPPs to circulating granulocytes after IFNg stimulation using lineage-tracing, thereby revealing which of these HSPC subtypes is most potent as a source of neutrophils. In Aim 2, we will evaluate IFNg-inducible factors for their role in HSPC differentiation using loss of function, xenotransplant, and functional biochemical studies. Finally, in Aim 3, we will test the utility of IFNg-induced HSPC myeloid differentiation in pathogen clearance using a mouse model of Group A Streptococcal myositis. Studies in Aim 3 will be informed by, but not dependent on, results of Aims 1 and 2. These studies will provide critical mechanistic data needed to design novel stem cell-based therapies for neutropenic fever and may reveal new insights into bone marrow failure syndromes that result from excessive inflammation.

项目总结/摘要 中性粒细胞减少症是一种特定白色血细胞缺乏症，是化疗的常见副作用， 患者死于机会性感染的风险很高。恢复中性粒细胞的现有方法，包括 G-CSF给药和粒细胞输注未产生明显的结局改善， 需要采取一些办法。白色血细胞是骨髓造血干细胞和祖细胞的产物 细胞（HSPC）可以通过循环炎症信号触发分裂和分化。我们事先 研究表明，炎症细胞因子干扰素γ（IFNg）是造血干细胞的有效刺激物， 干细胞（HSC）分裂和髓样分化。然而，持续的IFNg暴露抑制HSC自我更新， 最终导致骨髓衰竭无论是HSC还是它们的后代，多能祖细胞（MPP）， 是否对IFNg有同样的反应尚不清楚。此外，缺乏对信号传导的分子理解， 由IFNg诱导的促进HSPC分化的途径对利用HSPC的促免疫功能构成障碍。 IFNg，同时防止有害影响。在初步工作中，我们鉴定了IFNg在HSC中诱导的基因， 刺激，我们通过功能获得和丧失的研究表明，一个典型的基因可以关键地调节 HSPC分化。因此，我们假设IFN-γ诱导的转录变化可用于激活 静止的HSC产生更多的中性粒细胞，从而改善感染后的恢复。其基本原理是 HSC中特异性IFNg靶点的调节诱导可以增强短期骨髓生成， 长期破坏骨髓功能设计了三个目标来表征动力学，机制， 和IFNg依赖性HSPC分化的结果。在目标1中，我们将测量HSC的贡献 与使用谱系追踪的IFNg刺激后循环粒细胞的MPP相比， 在这些HSPC亚型中，作为中性粒细胞的来源最有效。在目标2中，我们将评估IFN-γ诱导的 使用功能丧失、异种移植和功能性生化指标评估其在HSPC分化中的作用 问题研究最后，在目标3中，我们将测试IFN g诱导的HSPC髓样分化在病原体中的效用。 使用A组链球菌性肌炎的小鼠模型进行清除。目标3中的研究将由以下方面提供信息，但 不依赖于目标1和2的结果。这些研究将提供关键的机械数据， 设计新的基于干细胞的治疗方法来治疗贫血热，并可能揭示骨髓的新见解 由过度炎症引起的衰竭综合征。