Functional interrogation of sensory neurons in inflammation

炎症中感觉神经元的功能询问

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要：慢性炎症性疾病折磨数百万美国人和毁灭性的伯恩斯关于病人的生活。缺乏对这些疾病的有效治疗方法，部分是因为多细胞身体系统（例如外周神经和免疫系统）之间的相互作用，可驱动注射知之甚少。例如，众所周知，感觉神经元在多种通过调节免疫反应来炎症疾病。特定的神经元亚型和分子导致这一贡献的机制尚不清楚。我的研究的总体目标是阐明精度周围感觉神经元影响的机制会影响炎症性疾病的发病机理皮肤和内脏器官以及感官神经元如何受到免疫系统影响。亚型的检测瘙痒（prriceptor）的感觉神经元表达了许多用于促炎和的受体免疫调节分子。这是这些培养基是精心策划多细胞的有吸引力的候选人炎症期间的相互作用。但是，这些特定感觉神经元在炎症性疾病中的作用是直到最近，还没有研究这些精确靶向这些神经元的工具。弥合这个差距知识，该提案将阐明培养基对不同炎症状态的贡献。拟议的研究将使用小鼠模型中的遗传和病毒方法来询问Pruceptor功能有选择地靶向和消灭这些神经元，并测量这些操纵对小鼠模型的影响炎症性疾病。具体而言，我将检验以下假设，即Pruceptors作为多型传感器厌恶化学，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，我将利用我久经考验的往绩来研究神经免疫我正在学习与创新技术的相互作用，我正在学习靶向和操纵感官的特定子集神经元，最终在炎症中绘制并阐明多细胞电路。 AIM 1将确定培养基对慢性瘙痒诱发的皮肤感染的贡献，通过结合病毒和遗传方法有选择地烧掉具有行为，免疫学，电生理和转录组读取的培养基出于了解培养基如何为皮肤感染做出贡献。作为分子相似的感觉神经元未知功能也支配了肠道，AIM 2将把这种方法转化为胃肠道的研究使用胃炎模型的炎症和肠道功能。我将把K99阶段的一部分用于职业发展活动，例如心理，在会议上介绍和发表研究文章。一部分这两个目标都将延续到该奖项的独立R00阶段。该建议将提供基本洞察以神经为重点的慢性炎症性疾病的多细胞相互作用看法。在Scripps研究所的帮助下成功执行该培训计划将准备我领导一个独立的研究计划。