The Role of the OLAM System in Burn Pain

OLAM 系统在烧伤疼痛中的作用

• 批准号: 8526898
• 负责人: Dustin Pepper Green
• 金额: $ 2.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526898
• 关键词: Address; Adverse effects; Afferent Neurons; Agonist; Analgesics; Anesthetics; Burn injury; Burning Pain; Capsaicin; Chemicals; Cytochrome P450; Data; Development; Electrophysiology (science); Enzymes; Family member; Future; Gated Ion Channel; Generations; Healthcare; Heating; Hospitalization; Hyperalgesia; In Vitro; Inflammatory; Injury; Ion Channel; Knowledge; Learning; Ligands; Light; Linoleic Acids; Mechanics; Mediating; Methods; Neurons; Nociception; Nociceptors; Pain; Patients; Peripheral; Physiological; Play; Population; Pre-Clinical Model; Protein Isoforms; Publishing; Research; Role; Stimulus; System; Techniques; Testing; Therapeutic; Tissues; Training; Vanilloid; allodynia; base; career; fundamental research; heat injury; innovation; knockout animal; multidisciplinary; novel; novel therapeutic intervention; pain receptor; patch clamp; public health relevance; receptor; skills; spontaneous pain; tool

DESCRIPTION (provided by applicant): It has been estimated that 2 million burn injuries occur yearly in the US, with ~15% of these injuries requiring hospitalization. The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of both mechanical and thermal allodynia and hyperalgesia. Thus, there is a compelling need for fundamental research aimed at understanding mechanisms of burn pain and in identifying potentially novel therapeutic approaches for treating it. A prominent member of the family of transient receptor potential (TRP) ligand-gated ion channels is the TRP vanilloid subfamily 1 (TRPV1) ion channel, and is expressed on a major subpopulation of nociceptive neurons. TRPV1 transduces various noxious physical and chemical stimuli applied to peripheral tissues. The TRPV1 ion channel plays a critical role in detecting many of these stimuli, including noxious heat, and contributes to heat hyperalgesia. The role of the TRPV1 receptor in mediating pain post burn injury is incompletely understood. Thus, further research on the mechanisms by which TRPV1 contributes to post-burn pain addresses an important gap in knowledge and may offer innovative approaches for treating the post-burn patient. Our lab has previously published data revealing a novel class of endogenous TRPV1 agonists, the oxidized linoleic acid metabolites (OLAMs), which are released upon thermal and inflammatory tissue injury. More recent preliminary studies have identified the cytochrome P450 (CYP) enzyme system in mediating the release of OLAMs from cultured neurons exposed to linoleic acid. Based upon these studies, as well as additional results presented as Preliminary Data, we propose that thermal injury leads to persistent activation of a CYP system leading to generation of oxidative metabolites of linoleic acid (OLAMs) and activation of TRPV1. The following specific aims will test this innovative hypothesis: Specific Aim 1 Determine whether thermal injury activates capsaicin-sensitive nociceptors via CYP mediated release of OLAMs. Specific Aim 1 uses in vitro cellular methods to evaluate the hypothesis that the OLAM system activates TRPV1 after peripheral burn injury. Aim 1 affords the opportunity to learn patch clamp electrophysiology, a method providing a valuable tool in my future career as a neurobiologist. Specific Aim 2 Identify CYP enzymes that is up-regulated in sensory neurons after thermal injury. Specific Aim 2 will identify and characterize CYP isoforms that are up-regulated in sensory neurons after burn injury. This Aim provides an excellent opportunity to learn both qRT-PCR as well as intracellular immunoneutralization, two techniques which will strengthen my future career as a neurobiologist.

描述（由申请人提供）：据估计，美国每年发生200万例烧伤，其中约15%需要住院治疗。烧伤患者的主要主诉是强烈的，通常是毁灭性的自发疼痛，并伴有持续的机械和热异常性疼痛和痛觉过敏。因此，迫切需要进行基础研究，以了解烧伤疼痛的机制，并确定潜在的新型治疗方法。瞬时受体电位（TRP）配体门控离子通道家族的一个重要成员是TRP香草蛋白亚家族1 （TRPV1）离子通道，并在伤害性神经元的主要亚群中表达。TRPV1可传导外周组织的各种有害物理和化学刺激。TRPV1离子通道在检测许多这些刺激中起着关键作用，包括有害的热，并有助于热痛觉过敏。TRPV1受体在烧伤后疼痛介导中的作用尚不完全清楚。因此，对TRPV1促进烧伤后疼痛机制的进一步研究填补了一个重要的知识空白，并可能为治疗烧伤后患者提供创新的方法。我们的实验室之前发表的数据揭示了一类新的内源性TRPV1激动剂，氧化亚油酸代谢物（OLAMs），在热和炎症组织损伤时释放。最近的初步研究已经确定细胞色素P450 （CYP）酶系统介导暴露于亚油酸的培养神经元释放OLAMs。基于这些研究，以及其他初步数据，我们提出热损伤导致CYP系统的持续激活，导致亚油酸（OLAMs）氧化代谢物的产生和TRPV1的激活。以下具体目标将验证这一创新假设：具体目标1确定热损伤是否通过CYP介导的OLAMs释放激活辣椒素敏感伤害受体。特异性目的1使用体外细胞方法评估外周烧伤后OLAM系统激活TRPV1的假设。Aim 1提供了学习膜片钳电生理学的机会，这种方法为我未来作为神经生物学家的职业生涯提供了宝贵的工具。特异性目的2：确定热损伤后感觉神经元中上调的CYP酶。特异性Aim 2将鉴定和表征烧伤后感觉神经元中上调的CYP亚型。这个Aim提供了一个学习qRT-PCR和细胞内免疫中和的绝佳机会，这两种技术将加强我未来作为神经生物学家的职业生涯。