Microbiota-dependent regulation of primitive hematopoieses

项目摘要/摘要 骨髓抑制是长期服用抗生素的常见不良反应，可 反过来，患者面临着未来感染的巨大风险。共生肠道细菌的枯竭有 最近被发现是抗生素介导的骨髓抑制的近端原因，涉及 微生物群在维持正常造血中的作用。共生细菌，通过I型干扰素和 STAT1是干扰素信号下游的一个主要转录因子，对于促进正常的 造血祖细胞在骨髓中的功能。然而，因为肠道中的共生细菌是 骨髓远端间室的刺激效应，介导这些反应的细胞类型(S)为 未知。此外，I型干扰素信号维持造血的充分性，或哪种共生 细菌信号通路与这一途径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， 这项提议的目的是询问微生物群对 造血术。研究将确定哪些组织和细胞类型(S)的I型干扰素和STAT1信号是 需要促进造血，特别是通过分析不同组织中的STAT1磷酸化， 产生骨髓嵌合体，并测试条件基因敲除小鼠。I型干扰素的充分性 维持造血的信号将通过鉴定重组干扰素的潜力来确定 或干扰素刺激细菌产品，以挽救抗生素治疗的小鼠的造血。最后，这一点 该提案将询问STAT1与通过细菌产物受体NOD1的信号之间的相互作用， 因为两者都与微生物群介导的造血调控有关。实验将定义 这些免疫因素是否在相同的途径中起作用，并确定将微生物区系与 骨髓壁龛中的细胞因子和代谢物。 这些严谨的研究建立在已发表的和初步的数据基础上，以澄清机制 通过共生微生物群调节造血的基础。圆满完成这些目标 将作为未来研究的重要基础，以开发预防和治疗方法 抗生素相关的骨髓抑制。这项工作是梅根·巴尔德里奇博士与 华盛顿大学共生微生物群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凯瑟琳·金博士在 贝勒医学院，并利用这些互补的专业领域来探索 微生物组介导的造血调节。

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.