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STING & PAIN: exploring a viral signaling protein in nociception and neuropathy

刺

基本信息

批准号：
10195073
负责人：
Temugin Berta
金额：
$ 44.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-10-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195073
关键词：
2019-nCoV Ache Adaptor Signaling Protein Adoption Afferent Neurons Agonist Animal Model Antiviral Agents Attenuated Automobile Driving BAY 54-9085 Behavior Behavioral Assay Biochemical Breeding COVID-19 COVID-19 outbreak Calcium Cells Cisplatin Clinical Clinical Trials DNA Detection Development Disease Electrophysiology (science)Enzyme-Linked Immunosorbent Assay FDA approved Gene Activation Gene Expression Gene Proteins Genes Genetic Transcription Goals HIV Health Care Costs Human Hypersensitivity Immune Immune response Immunomodulators Infection Inflammation Inflammatory Injections Interferon Type I Knockout Mice Lead Link Measures Mechanics Messenger RNA Mitochondria Mitochondrial DNA Mus Names Neuroimmunomodulation Neurons Neuropathy Neuropeptides Nociception Oxidative Stress Pain Pain management Pathogen detection Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacology Population Positioning Attribute Protein Array Proteins Regulation Research Role STING1 gene Signaling Protein Specificity Spinal Ganglia Stimulator of Interferon Genes Symptoms Testing Time Tissues Translations Viral Virus Virus Diseases Work chronic pain common symptom conditional knockout economic cost experimental study inhibitor/antagonist innovation insight intradermal injection mitochondrial dysfunction mouse model neuroimmunology novel therapeutic intervention novel therapeutics painful neuropathy pandemic disease pathogen pathogenic virus protein function response therapeutic target transcriptome sequencing

项目摘要

ABSTRACT Pain hypersensitivity is an early symptom of viral infections. While pain usually subsides with the progression of most infections, in some cases viral infection and antiviral drugs cause painful peripheral neuropathies. Peripheral sensory neurons are often the first target of viruses and are increasingly recognized as active components in pathogen detection and defense. As such it should not be surprising to known that sensory neurons express several singling proteins associated with pathogen recognition, yet very little is known about the neuronal functions of these proteins. The main goal of this application is to determine if the viral signaling adaptor protein known as stimulator of interferon genes (STING) in peripheral sensory neurons is mechanistically linked to pain hypersensitivity and painful peripheral neuropathies. STING is ideally positioned to underly both symptoms because it has been involved in the detection of abnormal cytosolic DNA delivered by viral pathogens or leaked from damaged mitochondria, a hallmark of various peripheral neuropathies. Our preliminary studies demonstrate that STING is express in peripheral nociceptive neurons and its peripheral engagement with specific agonists induces pain hypersensitivity. Therefore, we hypothesize that STING expression in sensory neurons drives unconventional neuronal functions leading to pain hypersensitivity, and in maladaptive conditions to painful peripheral neuropathies. We will test this hypothesis with multiple and unique approaches including the use of a conditional knockout mouse line with specific suppression of STING in sensory neurons. Aim 1 will establish the neuronal role of STING in driving pain hypersensitivity as well as changes in neuronal activity, transcription and release of immune modulators. Aim 2 will explore the role of STING in the development of peripheral neuropathies and evaluate various STING inhibitors as novel therapeutic approaches. Given that STING is pivotal to respond to viral infection, detection of mitochondrial dysfunction, and our testing of multiple drugs with FDA approval or in clinical trials, we expect that this research holds great promise for the adoption and development of new therapies for pain and potentially viral infection.

摘要疼痛过敏是病毒感染的早期症状。而疼痛通常会随着疾病的进展而减轻大多数感染，在某些情况下，病毒感染和抗病毒药物会导致疼痛的周围神经病。外周感觉神经元通常是病毒的第一个目标，并且越来越多地被认为是活跃的病原体检测和防御中的组成部分。因此，知道这种感官并不令人惊讶神经元表达几种与病原体识别相关的单一蛋白，但对此知之甚少。这些蛋白质的神经功能。这个应用程序的主要目标是确定病毒信号是否在外周感觉神经元中被称为干扰素基因刺激物(STING)的接头蛋白从机制上讲与疼痛过敏症和痛苦的周围神经病有关。斯汀的理想定位是两者都比不上症状，因为它参与了病毒病原体传递的异常胞浆DNA的检测或者是从受损的线粒体泄漏出来的，线粒体是各种周围神经疾病的标志。我们的初步研究证明了刺痛在外周伤害性神经元中表达，并证明了其外周与特定的激动剂会引起疼痛过敏。因此，我们假设刺痛在感觉神经元中的表达驱动非常规神经功能，导致疼痛过敏，并在适应不良的情况下痛苦的外周神经病。我们将使用多种独特的方法来测试这一假设，包括使用特定抑制感觉神经元刺痛的条件性基因敲除小鼠品系。目标1将确定刺痛在驱动疼痛超敏反应以及神经元活动变化中的神经元作用，免疫调节剂的转录和释放。目标2将探讨STING在糖尿病发展中的作用并评估各种刺痛抑制剂作为新的治疗方法。考虑到 STING在应对病毒感染、检测线粒体功能障碍以及我们对多个已获得FDA批准或正在进行临床试验的药物，我们预计这项研究将极有希望被采用以及针对疼痛和潜在的病毒感染的新疗法的开发。