2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654974摘要：耳鳴產生的細胞學機制目前尚不完全清楚。許多動物實驗顯示NMDA受器、GABA 受器、血清素受器、多巴胺受器等的過度活化與刺激可能與耳鳴的產生有關。本團隊去年成功建置「主動避免測試」之耳鳴動物模式。並以此模式發現在水楊酸所引起的急性耳鳴中，動物的耳蝸、中腦神經核之COX-2、NMDA受器、TNF-?、interleukin 1? 等都有基因過度表現的情形。本計劃將聚焦於NMDA受器之活化。間質金屬蛋白酶 (Matrix metalloproteinase, MMP) 是一種需要鋅的蛋白酶，它可以透過不同機制抑制NMDA 受器之活化。本團隊已獲取特殊的MMP 基因剔除鼠。本計劃擬使用此種剔除鼠研究移除此種特殊蛋白，增強NMDA受器的活性對耳鳴產生的影響。實驗中將使用B6 鼠做為控制。將動物在「主動避免」耳鳴測試箱中訓練後，再暴露在急性耳鳴 (注射水楊酸) 及慢性耳鳴 (噪音暴露) 下，測量並比較二組耳鳴的嚴重程度。同時這二組老鼠耳蝸及中腦的各種基因及蛋白的表現及活化也會被測量。本計劃將能進一步確認NMDA 受器與急、慢性耳鳴的關係。也可能對將來研發治療耳鳴口服藥物有所貢獻。<br> Abstract: The exact cellular mechanisms of tinnitus generation are unknown. Over-activation and stimulation of NMDA, GABA, serotonin, dopamine, and acetylcholine receptors were suggested by different animal experiments. Our team has successfully established an animal model of tinnitus by using active avoidance paradigms. We also demonstrated the increased NMDA, COX-2, TNF-α, interleukin 1β gene expression of cochlea and midbrain in the salicylate-induced acute tinnitus. The purpose of the present project will be focused on the NMDA receptor. Matrix metalloproteinase (MMP) is a zinc dependent endopeptidase, which was able to inhibit the NMDA receptor activation through various mechanisms. We have obtained a MMP knock out mice. We intended to investigate the effects of removal the activity of proteinase on the development of acute and chronic tinnitus. These MMP knock out animals, together with the control B6 mice, will be trained for the active avoidance test. Successfully conditioned animals will be induced to have acute tinnitus by IP injection of salicylate and chronic tinnitus by repeated noise exposure. Tinnitus severity based on the active avoidance test will be compared for these groups. Also the gene and protein expression of various receptors will be examined in the cochlea and brainstem of these animals. This experiment will delineate the exact role of NMDA receptor activation and gene expression in tinnitus and will potentially be help in the development of oral medication for tinnitus.間質金屬蛋白酶耳鳴動物模氏基因轉殖鼠Matrix metalloproteinasetinnitusanimal modeltransgenetic mice