Sensory Neuron-Bacteria Interactions in Modulating Pain and the Host Microbiota

调节疼痛和宿主微生物群的感觉神经元-细菌相互作用

• 批准号: 9167647
• 负责人: Isaac Ming-Cheng Chiu
• 金额: $ 254.25万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167647
• 关键词: Address; Afferent Neurons; Award; Bacteria; Binding; Biological; Brain; Capsaicin; Cells; Chemicals; Development; Economic Burden; Food; Germ-Free; Health; Homeostasis; Host Defense; Human; Immune; Immunology; Infection; Inflammation; Lead; Ligands; Lymphatic Diseases; Mediating; Mediator of activation protein; Medical Economics; Microbe; Molecular; Nervous system structure; Neurobiology; Neurons; Nociceptors; Organism; Pain; Peripheral; Physiology; Play; Production; Protein Analysis; Public Health; Qualifying; Research; Role; Sensory; Signal Transduction; Skin; Stimulus; Techniques; Testing; Tissues; Training; Transgenic Organisms; United States National Institutes of Health; base; chronic pain; commensal microbes; economic cost; gut microbiota; in vivo; insight; microbial; microbiota; multi-electrode arrays; mustard oil; neurotransmission; novel; novel therapeutics; optogenetics; pathogen; relating to nervous system; release of sequestered calcium ion into cytoplasm; research study; socioeconomics; therapy development; willingness

PROJECT ABSTRACT Pain is a fundamental protective neuronal signal for organisms to avoid danger. Nociceptors are the specific subset of peripheral sensory neurons that detect harmful/noxious stimuli and transmit pain signals to the brain. Chronic pain is a major socio-economic burden, but the underlying molecular mechanisms are not well understood. I previously found that bacterial pathogens produced pain by directly activating nociceptor neurons during infection. Moreover, I found that nociceptors played a role in suppressing local immune cell recruitment and lymphadenopathy. These findings raise the possibility that the nervous system can play a direct participatory role in host defense. Nociceptor neurons densely innervate the skin and gut, which are heavily colonized by commensal bacteria. However, the bidirectional crosstalk between the tissue-resident microbes with the sensory nervous system is poorly understood. In this NIH Director's New Innovator Award, I test the hypothesis that molecular interactions between the host microbiota and nociceptor neurons play a key role in governing pain production and the composition of the microbiota. This research is motivated by basic questions about the role of host-microbe interactions that will help us gain insights into mammalian physiology: i) Do specific commensal gut or skin bacterial species (pathobionts or symbionts) set the threshold for nociceptor neuron activity and development of chronic pain? ii) Can we identify specific bacterial molecular mediators that modulate nociceptor neural activity and pain? iii) Do nociceptor-associated ligands in spicy foods (e.g. capsaicin, mustard oil) have a significant impact on the composition and quality of the microbiota? Iv) Do nociceptor neurons produce molecular mediators that directly impact the microbiota or tissue-resident immune cells? To address these questions, I will combine neurobiological, immunological, and microbiological approaches to analyze the reciprocal interactions between nociceptor neurons and the resident microbiota. Germ-free and bacterial monocolonization experiments will determine if distinct symbiotic or pathobiotic commensal bacterial strains influence the development of pain. Neuronal calcium flux, multi-electrode array analysis, and protein chemical techniques will define the bacterial mediators that modulate nociceptor activity. These analyses will lead to the identification of potential novel molecular mediators of pain. Conversely, I will analyze if nociceptor activity in vivo plays a role in regulating the host microbiota. Using transgenic, pharmacological, and optogenetic strategies to specifically deplete, activate or silence nociceptors, I will ascertain whether sensory neurons modulate the composition of the skin and gut microbiota. Based on my foundational training in Immunology and Neurobiology, along with the ability to carry out cross-disciplinary scientific approaches, I am uniquely qualified to lead this effort. I have demonstrated a willingness to challenge convential paradigms, focusing my research on questions that have potential impacts on human health. With this proposed NIH Director's New Innovator Award, I will carry out studies to produce novel insights into host- microbe interactions facilitating the development of treatments for chronic pain and microbial dysbiosis.

项目摘要 疼痛是生物体避免危险的基本保护性神经信号。伤害感受器是特定的 周围感觉神经元的子集，可检测有害/有害刺激并向大脑传输疼痛信号。 慢性疼痛是主要的社会经济负担，但其潜在的分子机制尚不明确 明白了。我之前发现细菌病原体通过直接激活伤害感受器来产生疼痛 感染期间的神经元。此外，我发现伤害感受器在抑制局部免疫细胞方面发挥了作用 募集和淋巴结肿大。这些发现提出了神经系统可以发挥作用的可能性 宿主防御中的直接参与作用。伤害感受器神经元密集地支配皮肤和肠道， 被共生细菌大量定植。然而，组织驻留之间的双向串扰 人们对微生物与感觉神经系统知之甚少。在这次 NIH 主任新创新奖中，我 检验宿主微生物群和伤害感受器神经元之间的分子相互作用发挥关键作用的假设 在控制疼痛产生和微生物群组成中的作用。这项研究的动机是基于基础 关于宿主-微生物相互作用的作用的问题将帮助我们深入了解哺乳动物的生理学： i) 特定的共生肠道或皮肤细菌种类（病原体或共生体）是否设定了阈值 伤害感受器神经元活动和慢性疼痛的发展？ ii) 我们能否识别特定的细菌分子 调节伤害感受器神经活动和疼痛的介质？ iii) 辣味中伤害感受器相关配体 食物（例如辣椒素、芥末油）对微生物群的组成和质量有显着影响吗？ IV) 伤害感受器神经元是否产生直接影响微生物群或组织驻留的分子介质 免疫细胞？为了解决这些问题，我将结合神经生物学、免疫学和微生物学 分析伤害感受器神经元与常驻微生物群之间相互作用的方法。 无菌和细菌单一定植实验将确定不同的共生或致病 共生菌株影响疼痛的发展。神经元钙通量，多电极阵列 分析和蛋白质化学技术将定义调节伤害感受器活性的细菌介质。 这些分析将导致潜在的新型疼痛分子介质的鉴定。相反，我会 分析体内伤害感受器活性是否在调节宿主微生物群中发挥作用。使用转基因技术， 专门消耗、激活或沉默伤害感受器的药理学和光遗传学策略，我会 确定感觉神经元是否调节皮肤和肠道微生物群的组成。根据我的 免疫学和神经生物学的基础培训，以及进行跨学科的能力 科学方法，我是领导这项工作的独特资格。我已经表现出了挑战的意愿 传统范式，将我的研究重点放在对人类健康有潜在影响的问题上。和 在这个拟议的 NIH 主任新创新者奖中，我将进行研究，以对宿主产生新颖的见解- 微生物相互作用促进慢性疼痛和微生物失调治疗的开发。