INTESTINAL MICROBIAL REGULATION OF ANTIVIRAL IMMUNITY

项目摘要 本提案的目标是描述一个5年计划，为阿什利斯蒂德，医学博士，博士，独立， 一位研究微生物组在抗病毒免疫中的作用的物理学家兼科学家。她以优异的成绩毕业 她毕业于杜克大学，获得生物学学位，并在 华盛顿大学医学院医学科学家培训计划。在完成她 在她的儿科重症监护奖学金期间，她加入了Thaddeus Stappenbeck博士的实验室， 她已经证明，基础I型干扰素信号的升高在免疫过程中对宿主具有保护作用。 流感感染。这一发现解决了流感领域的一个争议。她将这些研究 研究肠道微生物组在驱动全身干扰素水平中的作用以及 病毒感染这些调查结果是本提案目标的基础。 华盛顿大学医学院是Steed博士开展研究的典范 该平台具有悠久的NIH资助研究历史以及资源的广度和深度。有 正如斯蒂德博士的指导委员会和合作者所证明的那样， 结合了微生物学、免疫学、儿科学和医学部门的专业知识。博士 Stappenbeck是粘膜表面宿主-微生物相互作用领域的领导者;因此，他是一个理想的 Steed博士的导师，因为他有能力破译发病机制， 培养年轻科学家的记录。他的实验室是一个智力能量的训练中心， 致力于广泛而富有创造性的项目。斯蒂德博士将有多次机会在当地展示她的工作 在更大的科学界。她将参加研究生水平的课程，以提高她的知识， 微生物学和基因组学，并与她的合作者发展关键的技术技能。 博士Steed的近期目标是实现本提案中概述的目标。虽然很明显， 微生物组对于抵抗流感发病机制很重要，分子理解这种相互作用 仍然模糊。她最近发现了一种与微生物相关的代谢物脱氨基酪氨酸， 增强I型干扰素信号传导。这一发现表明，一种特定的微生物代谢产物可能介导了 微生物组的保护作用。通过完成拟议的目标，斯蒂德博士将1）检验以下假设： 脱氨基酪氨酸通过增强全身性干扰素信号传导保护免受流感发病，2）定义 脱氨基酪氨酸增强干扰素信号传导的机制，以及3）鉴定 产生脱氨基酪氨酸的微生物组。她的实验室最初的重点将是进一步描绘这些 这样的机制，从她的研究洞察力将转化为战略，旨在提高抵抗力， 病毒致病和增强抗病毒免疫。

PROJECT SUMMARY The goal of this proposal is to describe a 5-year plan to prepare Ashley Steed, MD, PhD, for independence as a physician-scientist studying the role of the microbiome in antiviral immunity. She graduated with distinction from Duke University with a degree in Biology and obtained her medical and research graduate degree from Washington University School of Medicine's Medical Scientist Training Program. After completing her residency and during her pediatric critical care fellowship, she joined Dr. Thaddeus Stappenbeck's laboratory, where she has demonstrated that elevated basal interferon type I signaling is protective to the host during influenza infection. This finding resolves a controversy in the influenza field. She has extended these studies to investigate the role of the enteric microbiome in driving systemic interferon levels and the consequences for viral infection. These findings serve as the basis for the aims in this proposal. Washington University School of Medicine is an exemplary location for Dr. Steed to develop her research platform with its longstanding history of NIH funded research and breadth and depth of resources. There is frequent crosstalk among departments, as Dr. Steed's mentoring committee and collaborators demonstrate, combining the expertise from the departments of Microbiology, Immunology, Pediatrics, and Medicine. Dr. Stappenbeck is a leader in the field of host-microbial interactions at mucosal surfaces; thus he is an ideal mentor for Dr. Steed because of his ability to decipher mechanisms of pathogenesis and his strong track record in training young scientists. His laboratory is a training hub of intellectual energy with a diverse group working on broad and creative projects. Dr. Steed will have multiple opportunities to present her work locally and in the larger scientific community. She will take graduate level classes to enhance her knowledge in microbiology and genomics and develop key technical skills with her collaborators. Dr. Steed's immediate goal is to fulfill the aims outlined in this proposal. While it is clear that the enteric microbiome is important for resistance to influenza pathogenesis, molecular understanding of this interaction remains obscure. She recently discovered a microbially-associated metabolite, desaminotyrosine, that enhances type I interferon signaling. This finding suggests that a specific microbial metabolite may mediate the protective effect of the microbiome. By completing the proposed aims, Dr. Steed will 1) test the hypothesis that desaminotyrosine protects from influenza pathogenesis by enhancing systemic interferon signaling, 2) define the mechanism by which desaminotyrosine augments interferon signaling, and 3) identify components of the microbiome that produce desaminotyrosine. Her laboratory's initial focus will be to further delineate these mechanisms such that insight from her research will translate to strategies aimed at improving resistance to viral pathogenesis and enhancing antiviral immunity.