Ionic mechanisms of TNFalpha-induced sensitization

TNFα诱导致敏的离子机制

• 批准号: 7633260
• 负责人: Maria Elena Morales
• 金额: $ 2.79万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633260
• 关键词: Accounting; Address; Affect; Afferent Neurons; Animal Model; Behavior assessment; Behavioral; Biochemical; Biological; Cells; Characteristics; Clinic; Data; Disease; Effectiveness; Generations; Human; Hypersensitivity; Immune; In Vitro; Infection; Inflammatory; Injection of therapeutic agent; Intestines; Ion Channel; Lead; Link; MAP Kinase Gene; MAPK14 gene; Measures; Mechanics; Mediating; Mediator of activation protein; Membrane; Mission; Mus; Neurons; Nociception; Nociceptors; Pain; Pathway interactions; Peripheral; Pharmaceutical Preparations; Preparation; Process; Property; Resistance; Rheumatoid Arthritis; Role; Signal Transduction; Sodium Channel; Spinal Ganglia; Stimulus; System; TNF gene; Testing; Tetrodotoxin; Training; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States National Institutes of Health; Wild Type Mouse; Work; behavioral sensitization; chronic pain; cytokine; human MAPK14 protein; in vivo; multidisciplinary; nociceptive response; patch clamp; research study; response; response to injury; therapeutic target

DESCRIPTION (provided by applicant): The main objective of this study is to identify the mechanism(s) by which tumor necrosis factor-?- (TNF??) induces hypersensitivity. TNF? has been identified as a pro-nociceptive, pro-inflammatory cytokine, and anti-TNF? agents are currently used to treat painful inflammatory conditions which may, in part, be due to modulation of nociceptive signaling. The mechanism by which TNF? modulates nociception remains unknown. Recent work has demonstrated TNF? modulation of the tetrodotoxin-resistant Na+ channel a subunit, Nav1.8. This channel is primarily found in sensory neurons that detect painful stimuli, the primary afferent nociceptors, and is capable of altering excitability of dorsal root ganglia (DRG) neurons, a mechanism that could underlie behavioral hypersensitivity. Therefore, this proposal aims to examine the role of Nav1.8 in TNF? -induced behavioral hypersensitivity, to determine whether TNF? modulates DRG excitability, and to identify the necessity of Nav1.8 in this process. To this end, the proposed experiments will test the necessity of Nav1.8 in TNF? -induced mechanical and thermal hypersensitivity in vivo by behavioral assessment of hypersensitivity in Nav1.8-/- and wild-type littermate mice after intraplantar injection of TNF?. Further, because increased excitability is a mechanism by which hypersensitivity can be maintained, TNF? modulation of DRG excitability in vitro will be examined. These experiments will measure TNF? -induced alterations in excitability and examine the role of p38 MAPK in this process. Finally, the proposed experiments will then test the necessity of Nav1.8 in TNF? -induced modulation of DRG excitability by electrophysiological assessment of various membrane and AP properties in Nav1.8-/- and wild type DRG neurons. In accordance with the mission of the NIH, these studies are part of the long-term objective of identifying new potential targets for the treatment of painful conditions by understanding the biological mechanisms that underlie these conditions. These experiments can lead to enhancements in the treatment of pain, which is a costly and debilitating condition affecting millions of people.????

描述（由申请方提供）：本研究的主要目的是确定肿瘤坏死因子-？- (TNF??)诱发超敏反应。肿瘤坏死因子已被确定为一个亲伤害，促炎细胞因子，抗肿瘤坏死因子？目前，药物用于治疗疼痛的炎性病症，所述疼痛的炎性病症可能部分是由于伤害感受信号的调节。TNF？调节伤害感受的机制仍不清楚。最近的研究表明，TNF？河豚毒素抗性Na+通道a亚基Nav1.8的调节。该通道主要存在于检测疼痛刺激的感觉神经元（初级传入伤害感受器）中，并且能够改变背根神经节（DRG）神经元的兴奋性，这是一种可能导致行为超敏反应的机制。因此，这项建议的目的是研究Nav1.8在TNF？诱导的行为超敏反应，以确定是否TNF？调节DRG兴奋性，并确定Nav1.8在此过程中的必要性。为此，拟议的实验将测试的必要性Nav1.8在TNF？足底注射TNF？后，通过对Nav1.8-/-和野生型同窝小鼠的超敏反应进行行为评估，在体内诱导机械和热超敏反应。此外，由于增加兴奋性是一种机制，通过这种机制可以维持超敏反应，TNF？将检查体外DRG兴奋性的调节。这些实验将测量TNF？诱导的兴奋性改变，并检查p38 MAPK在这一过程中的作用。最后，拟议的实验，然后将测试的必要性Nav1.8在TNF？通过对Nav1.8-/-和野生型DRG神经元中的各种膜和AP特性的电生理学评估，来诱导DRG兴奋性的调节。根据美国国立卫生研究院的使命，这些研究是通过了解这些疾病的生物学机制来确定治疗疼痛疾病的新的潜在目标的长期目标的一部分。这些实验可能会导致疼痛治疗的改善，疼痛是一种影响数百万人的昂贵且令人衰弱的疾病。