(PQ #10) Gut-brain interactions underlying chemotherapy-induced behavioral comorbidities

项目总结/摘要 关于肠道微生物组在持久和普遍的conse中的潜在作用知之甚少。 化疗对大脑和行为的顺序（例如，认知障碍）。长期目标是 工作是确定如何操纵机制的潜在衰弱的行为后遗症，由于 癌症治疗的预防或治疗效果。这个R 01项目是我们对NCI挑衅性的回应 问题10：微生物群如何影响癌症治疗的反应？这项工作的总体目标是 以确定肠道微生物组-大脑相互作用在化疗相关认知问题中的作用。的 该项目的中心假设是，化疗改变了肠道微生物群的多样性，从而导致 神经炎症和认知障碍。因此，这项工作的基本原理是，了解如何能够- cer治疗通过肠道微生物组改变脑功能将阐明新的，更有效的，非侵入性的 这是一项旨在提高这一快速增长的人口生活质量的干预目标。四个具体目标是支持， 使用乳腺癌的非转移性小鼠模型和乳腺癌模型来检验中心假设。 癌症患者。目的1是确定化疗诱导的肠道微生物组变化在治疗中的作用。 行为使用我们的小鼠癌症模型，我们将研究学习和记忆之间的关系， 和肠道微生物序列多样性。目标2将确定必要的- 肠道微生物组变化对化疗诱导行为的影响。我们实现这一目标的方法 是通过使用无微生物小鼠或 益生菌治疗目的3旨在确定肠道微生物组在化疗诱导的神经细胞凋亡中的作用。 与认知相关的生理变化。利用先前肠道操作的脑组织，细胞和分子 将采用神经生物学方法来确定肠道微生物组对大脑通路的影响， 调节癌症/化疗背景下的认知。最后，目标4是一个探索性的临床目标， 将这项工作转化为化疗治疗的乳腺癌人群。在这里，我们将确定临床- 化疗对肠道微生物组和行为的后果之间的纵向关系- 合并症。这项工作的贡献将是重大的，因为它将启动讨论的哈尔- 利用肠-脑相互作用治疗和理解常见的行为合并症， 以及其他慢性疾病。拟议的研究是创新的，因为它是一个发展和实质性的 基于新的变革性研究， 肠脑交流我们的团队和环境在俄亥俄州州立大学是独一无二的定位进行 这种结合的转化和临床方法，为这一高优先级和创新的研究奋进。 PI是新的早期研究者。

PROJECT SUMMARY/ABSTRACT Very little is known about the potential role of the gut microbiome in the enduring and prevalent conse- quences of chemotherapy on the brain and behavior (e.g., cognitive impairments). The long-term goal for this work is to determine how to manipulate the mechanisms underlying debilitating behavioral sequelae due to cancer treatments for preventative or therapeutic results. This R01 project is our response to NCI Provocative Question #10: How do microbiota affect the response to cancer therapies? The overall objective of this work is to determine the role of gut microbiome-brain interactions in chemotherapy-related cognitive problems. The central hypothesis for this project is that chemotherapy shifts diversity in the gut microbiota, which leads to neuroinflammation and cognitive impairments. Thus, the rationale for this work is that understanding how can- cer treatment alters brain function via the gut microbiome will elucidate novel, more effective, and non-invasive targets of intervention to improve quality of life in this rapidly-growing population. Four specific aims are pro- posed to test the central hypothesis using both a non-metastatic mouse model of breast cancer and breast cancer patients. Aim 1 is to determine the role of chemotherapy-induced changes in the gut microbiome on behavior. Using our mouse cancer model, we will study the relationship between learning and memory behav- ior and gut microbial sequence diversity with chemotherapy treatment. Aim 2 will identify the necessi- ty/sufficiency of changes in the gut microbiome on chemotherapy-induced behaviors. Our approach for this aim is to directly manipulate the gut microbiome in this mouse model through either the use of microbe-free mice or probiotic treatment. Aim 3 is designed to identify the role of the gut microbiome in chemotherapy-induced neu- ral alterations relevant to cognition. Using brain tissue from the prior gut manipulations, cellular and molecular neurobiological approaches will be taken to pinpoint the effects of the gut microbiome on brain pathways that regulate cognition in the context of cancer/chemotherapy. Finally, Aim 4 is an exploratory clinical aim for the translation of this work into a chemotherapy-treated breast cancer population. Here, we will determine the clini- cal longitudinal relationship between the consequences of chemotherapy on the gut microbiome and behavior- al comorbidities. The contribution of this work will be significant because it will launch the discussion of har- nessing gut-brain interactions for the treatment and understanding of behavioral comorbidities common to can- cer and other chronic diseases. The proposed research is innovative because it is an evolved and substantial departure from the existing approaches to the chemobrain problem based on new transformative research on gut-brain communication. Our team and environment at Ohio State University is uniquely positioned to carry out this combined translational and clinical approach for this high-priority and innovative research endeavor. The PI is a New and Early Investigator.