探討G蛋白耦合受體TDAG8及酸敏感離子通道3調控神經病變痛的機制;The Modulatory Mechanism of Tdag8 and Asic3 in Neuropathic Pain

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题名:	探討G蛋白耦合受體TDAG8及酸敏感離子通道3調控神經病變痛的機制;The Modulatory Mechanism of Tdag8 and Asic3 in Neuropathic Pain
作者:	孫維欣
贡献者:	國立中央大學生命科學系
关键词:	神經病變痛;G 蛋白耦合受體TDAG8;酸敏感離子通道3;G 蛋白訊息傳導;痛覺神經細胞;neuropathic pain;TDAG8;Acid-sensing ion channel 3;G-protein signaling;nociceptors
日期:	2018-12-19
上传时间:	2018-12-20 11:28:48 (UTC+8)
出版者:	科技部
摘要:	慢性疼痛若無有效紓解，將會嚴重影響個人生活品質及社會醫療成本。全球約有15 億人口受慢性疼痛所苦，其中3-4.5％為神經病變痛。最大止痛藥市場仍為美國，但亞太市場在2007-2015 成長快速。新止痛藥發展的方向主要為關節炎、癌症及神經病變痛，然目前治療藥物侷限於副作用大或療效短 (30-40% 神經病變痛病人對單ㄧ治療有50%止痛療效)。因之，瞭解慢性疼痛的分子機制且找到止痛藥標的基因，有助於新止痛藥的發展。神經病變痛是由於神經系統損傷或疾病而引發產生的慢性疼痛，常伴隨有發炎反應。組織酸化被認為是調控發炎反應，引發疼痛的主因，且疼痛的引發主要是由於痛覺神經細胞中酸敏性受體受到刺激而產生。發炎反應的免疫細胞的表現或聚集亦受到酸敏性受體所調控。之前雖有研究發現神經受傷後，背根神經節細胞中酸敏性離子通道基因表現及電流有變化，但哪一類型酸敏性離子通道影響疼痛行為且其分子機制並不清楚。本實驗室之前研究發現，慢性坐骨神經壓迫性損傷會引發長期性疼痛及發炎反應，小鼠缺乏酸敏性 G 蛋白偶合受體 (TDAG8) 會延緩慢性坐骨神經壓迫性損傷引發之長期性疼痛，然而小鼠缺乏酸敏性離子通道3 (ASIC3) 則會縮短慢性坐骨神經壓迫性損傷引發之長期性疼痛。因之，本計劃的目的即是探討G 蛋白偶合受體 (TDAG8) 和酸敏性離子通道3 (ASIC3) 調控神經病變痛之分子機制。此計劃是具有獨創性因為這是藉由單細胞影像技術、非病毒載體基因抑制技術與基因剔除小鼠技術，結合動物行為實驗，系統性研究酸敏性受體在神經病變痛中扮演的角色及其機制，且釐清控制神經病變痛持續性的因子。本計劃預期會產生下列結果：瞭解酸敏性受體TDAG8 及 ASIC3 如何調控疼痛啓動及持續性。本計劃所提供的知識將會有助於瞭解慢性疼痛的分子機制，進而有助於臨床止痛治療及藥物發展。 ;Chronic pain has a profound effect on the personal life and the society, when not effectively treated and relieved. Ｍore than 1.5 billion people worldwide suffer from chronic pain of varying degrees, with 3-4.5% of global population in neuropathic pain. Although the US still represents the largest regional market for pain management, Asia-Pacific is the fastest growing regional market during the 2007-2015 period. Major segments of pain market are arthritis, cancer pain, and neuropathic pain, but current treatments are limited by unacceptable side effects or short-term efficacy (only one-third of neuropathic pain patients are likely to achieve 50% pain relief with monotherapy). Understanding of the molecular mechanism of chronic pain is important to identify potential drug targets for development of clinical treatments. Neuropathic pain is one type of chronic pain that occurs as a consequence of a lesion or disease to the somatosensory nervous system. Inflammation is often accompanied with neuropathic pain. Local tissue acidosis is the major factor to regulate inflammation and induce pain. The degree of associated pain or discomfort is well correlated with the magnitude of acidification. This is attributable to direct excitation of primary sensory neurons that detect noxious stimuli by proton-sensing receptors. Acidosis also regulates recruitment or activation of immune cells through proton-sensing receptors. We have found that mice with chronic constriction injury (CCI) of the sciatic nerve displayed long-term unilateral mechanical hyperalgesia and thermal hyperalgesia. CCI mice also developed long-term inflammation. TDAG8, a proton-sensing G-protein-coupled receptor (GPCR), deficient mice delayed the onset of hyperalgesia, while ASIC3, a proton-sensing ion channel, deficient mice shortened hyperalgesia. Given that TDAG8 is involved in initiating acid-induced hyperalgesia and establishing hyperalgesic priming in inflammatory model, it is possibly that TDAG8 in neurons triggers the onset of hyperalgesia and regulates ASIC3 to establish hyperalgesic priming in CCI model. The objective of this application is to how TDAG8 and ASIC3 regulate pathogenesis and molecular mechanism of neuropathic pain. The proposed work is innovative, as it is the first study to elucidate the modulatory roles of TDAG8 and ASIC3 in the initiation or the maintenance of neuropathic pain using the non-viral gene silencing, gene knockout, single cell imaging techniques combined with animal behavioural tests. It is expected to yield the following outcomes: elucidation of TDAG8 and ASIC3 involvement and their molecular mechanism in neuropathic pain. These results will be significant because they are expected to facilitate understanding of molecular mechanisms of neuropathic pain and to advance the fields of pain research. In addition, it is expected that the results will present useful information for development of new treatments.
關聯:	財團法人國家實驗研究院科技政策研究與資訊中心
显示于类别:	[生命科學系] 研究計畫

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