- 學位論文
探討組織酸化對本體感覺神經元中牽引力學傳導的影響
Probing the Effect of Acidosis on Tether-Mode Mechanotransduction of Proprioceptors
摘要
背景： 受Martin Chalfie 對觸覺接受器神經元（TRNs）和機械活化通道研究的啟發，本研究聚焦於酸敏感離子通道（ASICs），特別是ASIC3，在背根神經節（DRG）內表達Parvalbumin的本體感受神經元中的機械轉導作用。有別於Piezo channel 在背根神經節中的直接接觸模式，本研究將「牽引力模型」來研究神經元機械感應。 方法： 本研究採用先進的機械力控制膜片鉗電生理技術、條件性基因敲除實驗，深入研究ASIC3在本體感知中的功能。引入使用聚二甲基矽氧烷（PDMS）覆蓋玻片的新方法模擬生理彈性，以準確研究這些特定DRG神經元的機械敏感性。 結果： 本研究結果中顯示了ASIC3在酸性條件下在機械轉導中的重要作用。在表達Parvalbumin的本體感受神經元中，ASIC3的基因敲除導致本體感知受損，以及因神經突伸長牽引的機械轉導受到破壞。同時使用ASIC3專一性抑制劑APETx2的應用凸顯了ASIC3通道的功能細節。APETx2的處理改變了這些神經元的機械敏感性，強調了ASIC3在牽引力模型機械感應中的關鍵作用，以及受到環境音子影響的調控能力，並指出ASIC家族內的多樣性功能。 結論： 本研究確立了ASIC3作為本體感受神經元中機械轉導的核心元素。APETx2的研究不僅強調了ASIC3在本體感知中的關鍵作用，還揭示了ASIC家族的異質性和廣泛的功能範疇。這種異質性表明ASIC通道在各種生理和病理條件下的複雜相互作用，突顯了它們作為感覺處理障礙治療的潛力。，考慮到ASIC通道多樣且細膩的角色這些發現為針對性介入機械感應轉導打開了新的視角。 關鍵字：酸敏感離子通道第三型、機械力傳導、本體感覺
並列摘要
Background: Inspiring by Martin Chalfie’s study of touch receptor neurons (TRNs) and mechanically activated ion channels, this research focuses on the role of Acid-Sensing Ion Channels (ASICs), especially ASIC3, in mechanotransduction within parvalbumin-expressing proprioceptive neurons in the dorsal root ganglia (DRG). The study contrasts the ''tether model'' of mechanosensation with the bilayer model represented by Piezo channels. Methods: Employing advanced electrophysiological techniques, genetic axonal tracing, and conditional knockout experiments, the research scrutinizes ASIC3''s function in proprioception. Introducing a novel method using polydimethylsiloxane (PDMS) coverslips simulates physiological elasticity, facilitating an accurate study of the mechanosensitivi6ty of these specific DRG neurons. Results: The study reveals ASIC3''s substantial role in mechanotransduction under acidotic conditions. In parvalbumin-expressing proprioceptors, ASIC3 knockout results in impaired proprioception and disrupted neurite stretch-induced mechanotransduction. The application of APETx2, an ASIC3 inhibitor, highlighted the functional nuances of ASIC3 channels. Treatment with APETx2 modified the mechanosensitivity of these neurons, emphasizing ASIC3''s critical role in the tether model of mechanosensation, regulation of acidosis in the microenvironment, and indicating the diverse functionality within the ASIC family. Conclusion: This research establishes ASIC3 as a central element in mechanotransduction within proprioceptive neurons. The APETx2 study not only underscores ASIC3''s pivotal role in proprioception but also reveals the ASIC family''s heterogeneity and broad functional spectrum. This heterogeneity suggests a complex interplay of ASIC channels in various physiological and pathophysiological conditions, highlighting their potential as therapeutic targets for sensory processing disorders. The findings open new perspectives for targeted interventions in mechanosensory transduction, considering ASIC channels'' diverse and nuanced roles. Keywords: ASIC3, mechanotransduction, proprioception