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

（PQ

• 批准号: 9884548
• 负责人: LEAH M PYTER
• 金额: $ 39.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884548
• 关键词: Address; Affect; Anxiety; Area; Attention; Attenuated; Automobile Driving; Behavior; Behavioral; Biological; Brain; Breast Cancer Model; Breast Cancer Patient; Cancer Model; Cancer Patient; Chemotherapy-Oncologic Procedure; Chronic Disease; Clinical; Cognition; Cognitive; Data; Diarrhea; Environment; Goals; Growth Factor; Hippocampus (Brain); Hospital Costs; Impaired cognition; Impairment; Inflammation; Intervention; Investigation; Learning; Malignant Neoplasms; Memory; Mental Depression; Mental Health; Microbe; Microglia; Molecular; Moods; Mus; Nausea; Neurobiology; Nonmetastatic; Ohio; Outcome; Palate; Population; Positioning Attribute; Preventive treatment; Probiotics; Public Health; Quality of life; Research; Research Personnel; Rodent; Role; Survivors; Symptoms; Testing; Therapeutic; Time; Toxic effect; Translating; Translations; Universities; Work; base; behavior influence; brain behavior; brain pathway; brain tissue; cancer therapy; chemobrain; chemotherapy; cognitive ability; cognitive function; comorbidity; cost; design; falls; gut bacteria; gut microbiome; gut microbiota; gut-brain axis; improved; inflammatory marker; innovation; malignant breast neoplasm; microbial; microbiota; mouse model; neurobiological mechanism; neurogenesis; neuroinflammation; novel; relating to nervous system; response; tumor

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.

项目摘要/摘要 关于肠道微生物组在持久和普遍的孔隙中的潜在作用知之甚少 对大脑和行为的化学疗法的问题（例如，认知障碍）。这个长期目标 工作是确定如何操纵由于行为后遗症的衰弱的机制 预防或治疗结果的癌症治疗。这个R01项目是我们对NCI挑衅性的回应 问题＃10：微生物群如何影响对癌症疗法的反应？这项工作的总体目标是 确定肠道微生物组 - 脑相互作用在与化学疗法相关的认知问题中的作用。这 该项目的中心假设是化学疗法会改变肠道菌群的多样性，从而导致 神经炎症和认知障碍。因此，这项工作的理由是了解如何 CER治疗通过肠道微生物组来改变大脑功能，将阐明新颖，更有效和无创的 干预措施的目标是改善这种快速增长的人群的生活质量。四个具体目标是 摆姿势使用非转移小鼠乳腺癌和乳房模型测试中心假设 癌症患者。 AIM 1是确定化学疗法诱导的肠道微生物组变化的作用 行为。使用我们的小鼠癌症模型，我们将研究学习与记忆行为之间的关系 - IOR和肠道微生物序列多样性通过化学疗法治疗。 AIM 2将确定必要 肠道微生物组在化学疗法诱导的行为上的变化。我们实现这个目标的方法 是通过使用不含微生物的小鼠或 益生菌治疗。 AIM 3旨在确定肠道微生物组在化学疗法诱导的NEU-中的作用 与认知相关的RAL改变。使用先前的肠道操纵，细胞和分子的脑组织 将采用神经生物学方法来查明肠道微生物组对脑途径的影响 在癌症/化学疗法的背景下调节认知。最后，AIM 4是探索性的临床目的 将这项工作翻译成化学疗法治疗的乳腺癌人群。在这里，我们将确定临床 化学疗法对肠道微生物组的后果与行为 - 合并症。这项工作的贡献将是重要的，因为它将启动有关Har-的讨论 对肠道相互作用进行处理，以治疗和理解可以证明的行为合并症 CER和其他慢性疾病。拟议的研究具有创新性，因为它是进化而实质性的 基于有关新的变革性研究，从现有的方法偏离了Chemobrain问题 肠道沟通。我们在俄亥俄州立大学的团队和环境独特地携带 为这项高优先级和创新的研究努力提供了这种结合的翻译和临床方法。 PI是一个新的和早期的调查员。