Functional interrogation of sensory neurons in inflammation

炎症中感觉神经元的功能询问

• 批准号: 10723822
• 负责人: Rose Z Hill
• 金额: $ 11.99万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723822
• 关键词: Ablation; Address; Adolescent; Afferent Neurons; Agonist; American; Animals; Award; Back; Bacterial Gastritis; Behavior; Behavioral; Cells; Chemicals; Chronic; Cues; Cutaneous; Data; Data Set; Dedications; Development; Disease; Dissociation; Electrophysiology (science); Functional disorder; Future; Gastritis; Gastrointestinal Transit; Gastrointestinal tract structure; Gene Expression; Genetic; Genetic Models; Genetic Transcription; Goals; Health; Histologic; Histology; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Interleukins; Knockout Mice; Knowledge; Label; Lead; Learning; Leukotriene C4; Lipids; Maps; Measures; Mechanics; Mediating; Mediator; Mentors; Modeling; Molecular; Mus; Nature; Nervous System; Neuroimmune; Neurons; Neuropeptides; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nervous System; Phase; Physiological; Physiology; Piezo 1 ion channel; Play; Positioning Attribute; Pruritus; Publishing; Pylorus; Receptor Activation; Reporter; Research; Research Institute; Role; Sensory Ganglia; Signal Pathway; Signal Transduction; Skin; Sphingosine-1-Phosphate Receptor; Spinal; Stimulus; Stomach; Techniques; Testing; Tissues; Training; Translating; Validation; Vertebral column; Viral; Visceral; Work; body system; candidate identification; career development; chronic inflammatory disease; chronic itch; combat; conditional knockout; detection platform; effective therapy; experimental study; genetic approach; immune cell infiltrate; immunoregulation; improved; innovation; insight; mechanical signal; mechanical stimulus; mouse model; nerve supply; neuronal excitability; neuronal patterning; novel; novel therapeutics; programs; receptor; sensor; skin disorder; symposium; tool; transcriptome sequencing; transcriptomics; translational potential

PROJECT SUMMARY: Chronic inflammatory diseases afflict millions of Americans and place devasting burdens on patient’s lives. Effective treatments for these disorders are lacking, partly because the multicellular interactions between bodily systems (e.g. the peripheral nervous and immune systems) that drive inflammation are poorly understood. For example, it is known that sensory neurons play context-dependent roles in a variety of inflammatory disorders by modulating the immune response. The specific neuronal subtypes and molecular mechanisms that contribute to this remain unclear. The overarching goal of my research is to unravel the precise mechanisms by which peripheral sensory neurons influence the pathogenesis of inflammatory diseases of the skin and visceral organs and how sensory neurons are in turn influenced by the immune system. A subtype of sensory neuron that detects itch (pruriceptors), expresses a number of receptors for pro-inflammatory and immunomodulatory molecules. Thus, these pruriceptors are attractive candidates for orchestrating multicellular interactions during inflammation. However, the role of these specific sensory neurons in inflammatory disease is unstudied as, until recently, the tools to precisely target these neurons were lacking. To bridge this gap in knowledge, this proposal will elucidate the contribution of pruriceptors to distinct inflammatory states. The proposed research will interrogate pruriceptor function using genetic and viral approaches in mouse models to selectively target and ablate these neurons and measure the effects of these manipulations on mouse models of inflammatory diseases. Specifically, I will test the hypothesis that pruriceptors, as polymodal sensors of aversive chemical, mechanical, and immune stimuli, drive hypersensitivity and local inflammatory responses in a context-specific manner. During the K99 phase, I will leverage my proven track record in studying neuroimmune interactions with innovative techniques I am learning to target and manipulate specific subsets of sensory neurons and ultimately map and elucidate multicellular circuits in inflammation. Aim 1 will establish th e contributions of pruriceptors to chronic itch-evoked skin inflammation by combining viral and genetic approaches to selectively ablate pruriceptors with behavioral, immunological, electrophysiological, and transcriptomic read- outs to understand how pruriceptors contribute to skin inflammation. As molecularly similar sensory neurons of unknown function also innervate the gut, Aim 2 will translate this approach to the study of gastrointestinal tract inflammation and gut function using a model of gastritis. I will dedicate part of the K99 phase to career development activities such as mentoring, presenting at conferences, and publishing research articles. A portion of both Aims will carry over into the independent R00 phase of the award. This proposal will provide fundamental insights into the multicellular interactions underlying chronic inflammatory disease from a neuron-focused perspective. Successfully executing this training plan with the help of The Scripps Research Institute will prepare me to lead an independent research program.

项目概要：慢性炎症性疾病折磨着数百万美国人，给他们带来了毁灭性的负担。 病人的生命。缺乏对这些疾病的有效治疗，部分原因是多细胞 驱动炎症的身体系统（如外周神经和免疫系统）之间的相互作用 我们对此知之甚少。例如，已知感觉神经元在多种神经系统中发挥依赖于上下文的作用。 通过调节免疫反应来治疗炎症性疾病。特定的神经元亚型和分子 造成这种情况的机制尚不清楚。我研究的首要目标是 外周感觉神经元影响炎症性疾病发病机制的机制 皮肤和内脏器官以及感觉神经元如何反过来受到免疫系统的影响。的子类型 感觉神经元，检测瘙痒（瘙痒感受器），表达许多促炎和 免疫调节分子。因此，这些受体是协调多细胞 炎症过程中的相互作用然而，这些特定的感觉神经元在炎症性疾病中的作用是不确定的。 由于直到最近还缺乏精确靶向这些神经元的工具，为了弥合这一差距， 知识，这一建议将阐明的贡献，不同的炎症状态的受体。的 拟议中的研究将在小鼠模型中使用遗传和病毒方法来询问受体功能， 选择性地靶向和消融这些神经元，并测量这些操作对小鼠模型的影响 炎症性疾病的症状。具体地说，我将测试的假设，作为多模态传感器的神经元受体， 令人厌恶的化学、机械和免疫刺激，驱动超敏反应和局部炎症反应， 一种特定于上下文的方式。在K99阶段，我将利用我在研究神经免疫方面的良好记录， 与创新技术的互动我正在学习目标和操纵感官的特定子集 神经元，并最终映射和阐明炎症中的多细胞回路。目标1将建立 通过结合病毒和遗传学方法研究致痒感受器对慢性瘙痒诱发的皮肤炎症的作用 选择性地消融具有行为、免疫、电生理和转录组学读码的受体， 以了解细胞感受器如何促进皮肤炎症。作为分子相似的感觉神经元， 未知的功能也支配肠道，Aim 2将把这种方法转化为胃肠道的研究 炎症和肠道功能。我将把K99阶段的一部分奉献给职业生涯 发展活动，如指导，在会议上发言，并发表研究文章。一部分 这两个目标将结转到独立的R00阶段的奖励。该提案将提供基本的 从一个以神经元为中心的研究中深入了解慢性炎症性疾病的多细胞相互作用 perspective.在斯克里普斯研究所的帮助下，成功执行这一培训计划将为 让我领导一个独立的研究项目