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

项目摘要/摘要 关于肠道微生物群在持久和流行的肠道疾病中的潜在作用，人们知之甚少。 化疗对大脑和行为的影响(例如，认知障碍)。这方面的长期目标是 工作是确定如何操纵导致衰弱行为后遗症的机制 用于预防或治疗效果的癌症治疗。这个R01项目是我们对NCI挑衅的回应 问题10：微生物区系如何影响癌症治疗的反应？这项工作的总体目标是 确定肠道微生物-脑相互作用在化疗相关认知问题中的作用。这个 该项目的中心假设是化疗改变了肠道微生物区系的多样性，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- CER治疗通过肠道微生物组改变大脑功能将阐明新的、更有效的和非侵入性的 在这一快速增长的人口中改善生活质量的干预目标。四个具体目标是支持的- 提出使用乳腺癌和乳腺癌的非转移性小鼠模型来检验中心假设 癌症患者。目的1是确定化疗引起的肠道微生物群变化对 行为。利用我们的小鼠癌症模型，我们将研究学习和记忆行为之间的关系- 化疗后肠道微生物序列多样性与IOR的关系。目标2将确定必要的- 肠道微生物群变化对化疗诱导行为的影响。我们为实现这一目标而采取的方法 是通过使用无微生物的小鼠或通过使用 益生菌治疗。目的3是为了确定肠道微生物群在化疗诱导的神经营养不良中的作用。 与认知相关的神经中枢改变。使用之前肠道操作中的脑组织，细胞和分子 将采用神经生物学的方法来确定肠道微生物群对大脑通路的影响 在癌症/化疗的背景下调节认知。最后，目标4是一个探索性的临床目标 将这项工作转化为接受化疗的乳腺癌人群。在这里，我们将确定诊所- 化疗对肠道微生物群的影响与行为的纵向关系 阿尔茨海默病。这项工作的贡献将是重大的，因为它将启动对哈尔的讨论。 奈辛肠道-大脑交互作用用于治疗和了解CAN常见的行为共病 CER和其他慢性病。拟议的研究具有创新性，因为它是一项进化的和实质性的研究 基于新的变革性研究，背离了现有的解决化学污染问题的方法 直觉和大脑的交流。我们在俄亥俄州立大学的团队和环境具有得天独厚的优势 在这项高优先级和创新性的研究工作中，我们采用了翻译和临床相结合的方法。 私家侦探是一个新的和早期的调查者。

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.