Microbiota-dependent regulation of primitive hematopoieses

原始造血的微生物依赖调节

基本信息

批准号：
10293608
负责人：
Megan T Baldridge
金额：
$ 45.17万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-07 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10293608
关键词：
Adverse effects Affect Agonist Anemia Animals Antibiotic Therapy Antibiotics Area Bacteria Bacterial Infections Blood Bone Marrow Bone Marrow Cells Bone Marrow Suppression Cells Cephalosporins Chimera organism Clostridium Collaborations Complication Critical Pathways Data Defect Distal FLT3 ligand Future Gene Expression Profile Genes Germ-Free Growth Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Homeostasis IL7 gene Immune Immune Cell Suppression Immune system Immunologic Factors Individual Infection Innate Immune System Interferon Type I Interferons Intestines Knockout Mice Ligands Link Long-Term Effects Maintenance Mediating Medicine Molecular Mus Neutropenia Pancytopenia Pathway interactions Patients Penicillins Phenocopy Phosphorylation Physiological Preventive Production Publishing Recombinant Interferon Recombinants Regulation Reporting Risk Role STAT1 gene Signal Pathway Signal Transduction Spleen System Testing Therapeutic Tissues Trimethoprim-Sulfamethoxazole Universities Washington Work base cell type college combat commensal bacteria conditional knockout cytokine dysbiosis experimental study gut bacteria gut microbiome gut microbiota immunoregulation insight interferon alpha receptor medical schools metabolomics microbiome microbiota mouse model novel novel therapeutic intervention prevent receptor response side effect small molecule transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Bone marrow suppression is a common adverse effect of long-term antibiotic administration, which can in turn leave patients at substantial risk for future infections. Depletion of commensal intestinal bacteria has recently been uncovered as the proximal cause of antibiotic-mediated bone marrow suppression, implicating the microbiome in maintenance of normal hematopoiesis. Commensal bacteria, acting via type I interferon and STAT1, a major transcription factor downstream of interferon signaling, are necessary to promote the normal function of hematopoietic progenitors in the bone marrow. However, because commensal bacteria in the gut are stimulating effects in the distal compartment of the bone marrow, the cell type(s) mediating these responses are unknown. Further, the sufficiency of type I interferon signaling to maintain hematopoiesis, or which commensal bacterial signaling pathways interact with this pathway to drive hematopoiesis, are unknown. Using a murine model of antibiotic-mediated bone marrow suppression to explore these critical questions, this proposal aims to interrogate the pathways and mechanisms underlying the microbiome’s effects on hematopoiesis. Studies will identify in which tissue and cell type(s) type I interferon and STAT1 signaling are required to promote hematopoiesis, specifically by analyzing STAT1 phosphorylation in different tissues, generating bone marrow chimeras, and testing conditional knock-out mice. The sufficiency of type I interferon signaling to maintain hematopoiesis will be determined by characterizing the potential of recombinant interferons or interferon-stimulatory bacterial products to rescue hematopoiesis in antibiotic-treated mice. Finally, this proposal will interrogate interactions between STAT1 and signaling through NOD1, a bacterial product receptor, because both have been implicated in microbiome-mediated hematopoietic regulation. Experiments will define whether these immune factors act in the same pathway, and identify novel factors linking the microbiota with cytokines and metabolites in the bone marrow niche. These rigorous studies build upon both published and preliminary data to clarify the mechanisms underlying the regulation of hematopoiesis by the commensal microbiome. Successful completion of these aims will serve as a critical basis for future studies to develop preventive and therapeutic approaches to combat antibiotic-associated bone marrow suppression. This work is a close collaboration between Dr. Megan Baldridge, expert in the effects on the commensal microbiome on the innate immune system, at Washington University School of Medicine and Dr. Katherine King, expert in immunologic regulation of primitive hematopoiesis, at Baylor College of Medicine, and leverages these complementary areas of expertise to explore the novel field of microbiome-mediated hematopoietic regulation.

项目概要/摘要骨髓抑制是长期服用抗生素的常见不良反应，可导致进而使患者面临未来感染的巨大风险。最近被发现是抗生素介导的骨髓抑制的近端原因，表明维持正常造血的微生物组，通过 I 型干扰素和 STAT1 是干扰素信号传导下游的主要转录因子，对于促进正常的然而，由于肠道中的共生细菌是造血祖细胞的功能。骨髓远端室的刺激作用，介导这些反应的细胞类型是此外，I 型干扰素信号传导是否足以维持造血功能或共生作用尚不清楚。细菌信号通路与该通路相互作用以驱动造血，目前尚不清楚。使用抗生素介导的骨髓抑制的小鼠模型来探索这些关键问题，该提案旨在探究微生物组影响的途径和机制研究将确定 I 型干扰素和 STAT1 信号传导存在于哪些组织和细胞类型中。促进造血所需，特别是通过分析不同组织中的 STAT1 磷酸化，生成骨髓嵌合体，并测试条件敲除小鼠 I 型干扰素的充足性。维持造血功能的信号传导将通过表征重组干扰素的潜力来确定或干扰素刺激细菌产品来挽救抗生素治疗小鼠的造血功能。该提案将探讨 STAT1 和通过 NOD1（一种细菌产物受体）信号传导之间的相互作用，因为两者都与微生物介导的造血调节有关，实验将对其进行定义。这些免疫因子是否在同一途径中发挥作用，并确定将微生物群与免疫因子联系起来的新因子骨髓生态位中的细胞因子和代谢物。这些严格的研究建立在已发表的数据和初步数据的基础上，以阐明其机制共生微生物组对造血作用的调节是成功完成这些目标的基础。将作为未来研究开发预防和治疗方法的重要基础抗生素相关的骨髓抑制这项工作是 Megan Baldridge 博士的密切合作。华盛顿大学共生微生物组对先天免疫系统影响的专家医学院和原始造血免疫调节专家 Katherine King 博士贝勒医学院，并利用这些互补的专业领域来探索新的领域微生物组介导的造血调节。