Vanilloid Receptor VR1 in Osteoarthritis

香草酸受体 VR1 在骨关节炎中的作用

• 批准号: 7145936
• 负责人: JULI G VALTSCHANOFF
• 金额: $ 31.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145936
• 关键词: afferent nerve; inflammation; joints; neurons; neuropeptides; osteoarthritis; pain; receptor; role

DESCRIPTION (provided by applicant): This is a resubmission of a grant application reviewed during the June 2005 study session. The revised Specific Aims are designed to meet the suggestions of the study session and to reflect the new data obtained since the original submission. The research aims at elucidating the role of vanilloid receptor TRPV1 in the sensory nerves to the joints and in the pathophysiological mechanisms of chronic osteoarthritis. TRPV1, an ion channel on nerve fibers innervating the skin, is activated by noxious heat and capsaicin, as well as by mediators of inflammation and ischemia. TRPV1-positive nerve fibers have also been discovered in a variety of subcutaneous structures, including joints, consistent with other evidence implication capsaicin-sensitive afferents in joint inflammation of clinical significance. TRPV1 is expressed by afferents in joints different from those in the skin; since joints are not normally exposed to noxious heat or capsaicin, the role of TRPV1 in articular afferents is unknown. The first aim will be determine whether TRPV1-positive articular afferents selectively contain substance P and calcitonin gene-related peptide, two neuropeptides associated with nociception in cutaneous afferents, and whether they are sensitive to nerve growth factor. The second aim will be to assess the role of TRPV1 in the neurogenic release of peptides into the synovial fluid by comparing TRPV1-null mice and wide type controls. The third aim will be to use an animal model of chronic osteoarthritis to study how genetic deletion of TRPV1 Influences the pain-related behavior, severity of inflammation, and activation of a family of extracellularly-regulated kinases (ERK) in spinal neurons. The same model will also test the hypotheses that nerve growth factor-dependent upregulation of TRPV1 in primary afferent neurons contributes to the peripheral sensitization leading to the hyperalgesia or arthritis. The fourth aim will be test the hypothesis that activation of ERK in sensory neurons helps to mediate central sensitization in osteoarthritis by testing whether this sensitization is abolished in ERK-null mice or can be prevented by intrathecal application of an inhibitor of the ERK pathway.

描述（由申请人提供）：这是在2005年6月研究期间审查的赠款申请的重新提交。 修订后的特定目标旨在满足研究会议的建议，并反映以来最初提交以来获得的新数据。 该研究旨在阐明香草素受体TRPV1在感官神经中的作用，以及在慢性骨关节炎的关节和病理生理机制中的作用。 TRPV1是神经纤维上的一个离子通道，由有害的热和辣椒素以及炎症和缺血的介体激活。 TRPV1阳性神经纤维也已经在各种皮下结构中发现，包括关节，与其他证据含义的辣椒素敏感传入剂一致的关节炎症中的关节炎症具有临床意义的关节炎症。 TRPV1由与皮肤中不同的关节传入表示。由于关节通常不会暴露于有害热或辣椒素中，因此TRPV1在关节传入中的作用尚不清楚。 第一个目的是确定TRPV1阳性关节传入是否选择性地含有PESSS P和降钙素基因相关的肽，两种与皮肤传入中伤害感受相关的神经肽以及它们是否对神经生长因子敏感。 第二个目的是通过比较TRPV1-NULL小鼠和广泛的对照组来评估TRPV1在肽中的神经源性释放中的作用。 第三个目的是使用慢性骨关节炎的动物模型来研究TRPV1的遗传缺失如何影响与疼痛相关的行为，炎症的严重程度以及脊髓外管外激酶（ERK）家族的激活。 同一模型还将检验假设的假设，即在原发性传入神经元中TRPV1的神经生长因子依赖性上调有助于周围敏化，从而导致痛觉过敏或关节炎。 第四个目的是检验以下假设：ERK在感觉神经元中的激活有助于通过测试ERK-NULL小鼠中是否消除这种敏化的骨关节炎中的中心敏化，或者可以通过鞘内应用ERK途径的抑制剂来预防。