Role of TRPV channels in pain and temperature sensation

TRPV 通道在痛觉和温度觉中的作用

• 批准号: 7627210
• 负责人: Michael J Caterina
• 金额: $ 31.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627210
• 关键词: Acute; Address; Afferent Neurons; Analgesics; Behavioral; Biochemical; Biological Assay; Calcium; Cations; Cells; Clinical; Coculture Techniques; Communication; Conscious; Detection; Dominant-Negative Mutation; Epithelial; Esthesia; Gated Ion Channel; Genetically Engineered Mouse; Goals; Health; Heating; High temperature of physical object; Hypersensitivity; Image; In Vitro; Inflammation; Knockout Mice; Mechanics; Methods; Mus; Mutant Strains Mice; Nociception; Nociceptors; Pain; Perception; Peripheral Nervous System; Phenotype; Population; Proteins; Reporting; Research Personnel; Role; Skin; Stimulus; Subconscious; Swelling; TRPV channel; TRPV1 gene; Temperature; Testing; Thermal Hyperalgesias; Tissues; Transducers; Transgenic Mice; afferent nerve; base; cell type; chronic pain; keratinocyte; loss of function; nerve injury; overexpression; programs

DESCRIPTION (provided by applicant): Acute and chronic pain represent significant and under-treated health problems in the U.S. due, in part, to our incomplete understanding of the mechanisms by which the peripheral nervous system detects noxious stimuli. TRPV1 is a heat-gated ion channel required for some, but not all aspects of heat-evoked pain. Three related channels, TRPV2, TRPV3, and TRPV4, can also be activated by elevated temperatures and therefore may contribute to the detection of painful heat. TRPV2 is activated at very high temperatures (>52 degrees C) and expressed most highly in a subset of sensory neurons. TRPV3 and TRPV4 are activated at temperatures >32 degrees C. In the skin, TRPV3 and TRPV4 expression is most prominent in epithelial keratinocytes, raising the possibility that these cells participate in an indirect mode of thermosensation involving TRPV3 and TRPV4. TRPV2 and TRPV4 can also be activated by cell swelling, suggesting that they may participate in mechanosensation. This proposal is aimed at achieving the following goals: (1) To determine whether and how TRPV2 and TRPV4 contribute to the detection of painful and nonpainful thermal and mechanical stimuli. (2) To determine whether keratinocyte TRPV3 and TRPV4 contribute to noxious and/or innocuous thermosensation and mechanosensation. (3) To determine how keratinocytes communicate the presence of thermal stimuli to adjacent sensory neurons. To achieve these goals, TRPV2 and TRPV4 null mutant mice will be analyzed for acute responsiveness to mechanical and thermal stimuli and for enhancement of thermo- or mechanosensitivity following inflammation or nerve injury. Wild-type or dominant negative forms of TRPV3 or TRPV4 will be overexpressed selectively in keratinocytes and the effects on thermosensation evaluated behaviorally. Finally, biochemical electrophysiological, fluorescent calcium imaging, and behavioral methods will be used to identify molecules through which heat-exposed keratinocytes communicate with nearby sensory neurons.

描述（由申请人提供）：在美国，急性和慢性疼痛是严重且未得到充分治疗的健康问题，部分原因是我们对周围神经系统检测有害刺激的机制不完全了解。 TRPV1 是热诱发疼痛的某些方面（但不是所有方面）所需的热门控离子通道。三个相关通道 TRPV2、TRPV3 和 TRPV4 也可以被高温激活，因此可能有助于检测疼痛热。 TRPV2 在非常高的温度（> 52 摄氏度）下被激活，并在感觉神经元的子集中表达最高。 TRPV3 和 TRPV4 在温度 > 32 摄氏度时被激活。在皮肤中，TRPV3 和 TRPV4 表达在上皮角质形成细胞中最为突出，这提高了这些细胞参与涉及 TRPV3 和 TRPV4 的间接热感觉模式的可能性。 TRPV2 和 TRPV4 也可以被细胞肿胀激活，表明它们可能参与机械感觉。该提案旨在实现以下目标：（1）确定TRPV2和TRPV4是否以及如何有助于检测疼痛和非疼痛的热和机械刺激。 (2)确定角质形成细胞TRPV3和TRPV4是否有助于有害和/或无害的热感觉和机械感觉。 (3) 确定角质形成细胞如何将热刺激的存在传达给邻近的感觉神经元。为了实现这些目标，将分析 TRPV2 和 TRPV4 缺失突变小鼠对机械和热刺激的急性反应性，以及炎症或神经损伤后热或机械敏感性的增强。 TRPV3 或 TRPV4 的野生型或显性失活形式将在角质形成细胞中选择性过度表达，并通过行为评估对热感觉的影响。最后，生化电生理学、荧光钙成像和行为方法将用于识别热暴露的角质形成细胞与附近感觉神经元进行交流的分子。

项目成果

TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception.

• DOI: 10.1523/jneurosci.1384-09.2011
• 发表时间: 2011-08-10
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Park U;Vastani N;Guan Y;Raja SN;Koltzenburg M;Caterina MJ
• 通讯作者: Caterina MJ

TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation.

• DOI: 10.1186/1744-8069-7-37
• 发表时间: 2011-05-17
• 期刊: Molecular pain
• 影响因子: 3.3
• 作者: Huang SM;Li X;Yu Y;Wang J;Caterina MJ
• 通讯作者: Caterina MJ