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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要中性粒细胞减少症是某些白细胞的缺乏，是化疗的常见副作用。患者因机会性感染而死亡的风险很高。恢复中性粒细胞的现有方法包括 G-CSF 给药和粒细胞输注尚未对结果产生明显改善，而新的需要采取一些方法。白细胞是骨髓造血干细胞和祖细胞的产物可以通过循环炎症信号触发分裂和分化的细胞（HSPC）。我们之前的研究表明，炎症细胞因子干扰素γ (IFNg) 是造血的有效刺激物。干细胞（HSC）分裂和骨髓分化。然而，持续的 IFNg 暴露会抑制 HSC 的自我更新，最终导致骨髓衰竭。无论是 HSC 还是它们的后代，即多能祖细胞 (MPP)，对 IFNg 是否同样敏感尚不清楚。此外，缺乏对信号传导的分子理解 IFNg 诱导的促进 HSPC 分化的途径对利用 IFNg 的促免疫功能构成了障碍 IFNg 同时防止有害作用。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，一个示范基因可以严格调节 HSPC分化。因此，我们假设 IFNg 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，从而改善感染的恢复。理由是调节 HSC 中特定 IFNg 靶标的诱导可能会增强短期骨髓细胞生成，而无需破坏长期骨髓功能。设计了三个目标来表征动力学、机制、以及 IFNg 依赖性 HSPC 分化的结果。在目标 1 中，我们将衡量 HSC 的贡献使用谱系追踪将 IFNg 刺激后的 MPP 与循环粒细胞进行比较，从而揭示哪些这些 HSPC 亚型中的一种是最有效的中性粒细胞来源。在目标 2 中，我们将评估 IFNg 诱导型使用功能丧失、异种移植和功能生化来确定其在 HSPC 分化中的作用的因素研究。最后，在目标 3 中，我们将测试 IFNg 诱导的 HSPC 骨髓分化在病原体中的效用使用 A 组链球菌肌炎小鼠模型进行清除。目标 3 的研究将被告知，但是不依赖于目标 1 和 2 的结果。这些研究将提供所需的关键机制数据设计针对中性粒细胞减少性发热的新型干细胞疗法，并可能揭示对骨髓的新见解过度炎症导致的衰竭综合症。