Microbiota-dependent regulation of primitive hematopoieses

项目总结/摘要 骨髓抑制是长期使用抗生素的常见副作用， 这反过来又使患者处于未来感染相当大的风险中。肠道细菌的消耗 最近被发现是血小板介导的骨髓抑制的近端原因， 微生物组在维持正常造血中的作用。共生菌，通过I型干扰素起作用， STAT 1是干扰素信号传导下游的主要转录因子，是促进正常细胞增殖所必需的。 造血祖细胞在骨髓中的功能。然而，由于肠道中的肠道细菌 在骨髓远端隔室中的刺激作用，介导这些反应的细胞类型是 未知此外，I型干扰素信号传导维持造血的充分性，或I型干扰素信号传导维持造血的充分性， 细菌信号传导途径与该途径相互作用以驱动血细胞生成是未知的。 使用一个小鼠模型的血小板介导的骨髓抑制来探索这些关键问题， 该提案旨在探究微生物组对以下疾病影响的潜在途径和机制： 造血研究将确定I型干扰素和STAT 1信号传导在哪些组织和细胞类型中起作用。 需要促进造血，特别是通过分析STAT 1磷酸化在不同组织， 产生骨髓嵌合体，并测试条件性基因敲除小鼠。I型干扰素的充分性 维持造血的信号传导将通过表征重组干扰素 或干扰素刺激性细菌产物来拯救造血作用。最后 该提案将通过NOD 1，一种细菌产物受体， 因为两者都与微生物组介导的造血调节有关。实验将定义 这些免疫因子是否在同一途径中起作用，并确定将微生物群与 细胞因子和代谢物在骨髓生态位。 这些严谨的研究建立在已发表和初步数据的基础上，以阐明机制 这是通过肠道微生物组调节造血的基础。圆满完成这些目标 将作为未来研究的重要基础，以制定预防和治疗方法， 骨髓抑制这项工作是梅根·鲍德里奇博士， 他是华盛顿大学研究肠道微生物对先天免疫系统影响的专家 医学院和凯瑟琳金博士，在原始造血免疫调节专家，在 贝勒医学院，并利用这些互补的专业领域，探索新的领域， 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.