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 疼痛是生物体的基本保护性神经元信号，以避免危险。伤害感受器是特定的 检测有害/有害刺激并将疼痛信号传递到大脑的周围感觉神经元的子集。 慢性疼痛是一种主要的社会经济负担，但潜在的分子机制不好 理解。我以前发现细菌病原体通过直接激活伤害感受器产生疼痛 感染过程中的神经元。此外，我发现伤害感受器在抑制局部免疫细胞中发挥了作用 招募和淋巴结肿大。这些发现增加了神经系统可以发挥的可能性 在宿主防御中的直接参与角色。伤害感受器神经元密集地支配皮肤和肠道，这是 由共生细菌重殖。但是，组织居民之间的双向串扰 具有感官神经系统的微生物知之甚少。在NIH导演的新创新奖中，我 测试宿主微生物群和伤害感受器神经元之间的分子相互作用的假设发挥了钥匙 在治理疼痛产生和微生物群的组成中的作用。这项研究是由基本的动机 关于宿主 - 微生物相互作用的作用的问题，这将有助于我们了解哺乳动物生理学： i）做特定的共生肠道或皮肤细菌种类（病原体或共生物）设置阈值 伤害感受器神经元活性和慢性疼痛的发育？ ii）我们可以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体？ iii）在辛辣 食物（例如辣椒素，芥末油）对微生物群的组成和质量有重大影响吗？ iv）伤害感受器神经元会产生直接影响菌群或组织居民的分子介质 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驻留微生物群之间的相互相互作用的方法。 无菌和细菌单殖民化实验将确定是不同的共生或病原体的 共生细菌菌株会影响疼痛的发展。神经元钙通量，多电极阵列 分析，蛋白质化学技术将定义调节伤害感受活性的细菌介质。 这些分析将导致鉴定潜在的新型疼痛分子介质。相反，我会的 分析体内的伤害感受器活性在调节宿主微生物群中起作用。使用转基因， 专门耗尽，激活或沉默的伤害感受器的药理和光遗传学策略，我将 确定感觉神经元是否调节皮肤和肠道菌群的组成。基于我 免疫学和神经生物学的基础培训，以及进行跨学科的能力 科学的方法，我具有独特的资格来领导这项工作。我已经表现出挑战的意愿 令人信服的范式，将我的研究重点放在对人类健康有潜在影响的问题上。和 这项提议的NIH导演的新创新者奖，我将进行研究，以对主持人产生新颖的见解 - 微生物相互作用促进了慢性疼痛和微生物营养不良的治疗的发展。