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.

抽象的疼痛超敏反应是病毒感染的早期症状。疼痛通常会随着进展而消退大多数感染在某些情况下，病毒感染和抗病毒药会引起疼痛的周围神经病。外围感觉神经元通常是病毒的第一个靶标，并且越来越被认为是活跃的病原体检测和防御中的组成部分。因此，知道这种感觉就不足为奇了神经元表达几种与病原体识别相关的单一蛋白质，但对这些蛋白质的神经元功能。该应用程序的主要目标是确定病毒信号是否是否周围感觉神经元中称为干扰素基因刺激基因刺激剂的衔接蛋白在机械上是机械的与疼痛超敏反应和疼痛的周围神经病有关。刺是理想的位置症状是因为它参与了病毒病原体传递的异常胞质DNA的检测或从损坏的线粒体中泄漏，这是各种周围神经病的标志。我们的初步研究证明刺是在周围伤害性神经元中表达及其与特定的外围互动激动剂诱导疼痛超敏反应。因此，我们假设感觉神经元中的刺激表达驱动非常规神经元功能，导致疼痛超敏反应，并在适应不良的情况下疼痛的周围神经病。我们将使用多种和独特的方法来检验这一假设使用有条件的敲除小鼠线，并在感觉神经元中特异性抑制刺。目标1意志确定刺激在驱动疼痛超敏反应以及神经元活性的变化中的神经元作用，免疫调节剂的转录和释放。 AIM 2将探讨Sting在发展中的作用周围神经病并评估各种刺激抑制剂作为新型治疗方法。鉴于刺激对病毒感染，线粒体功能障碍的检测和我们对多个的测试至关重要获得FDA批准或临床试验的药物，我们希望这项研究对采用有很大的希望以及开发疼痛和潜在病毒感染的新疗法。