2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642832摘要：化學治療引起的神經病變是造成神經性疼痛的重要病因。最近十年來，標靶療法已成為化學治療的新策略，例如 bortezomib，然而其所造成的以疼痛為主要表徵的神經病變也是主要併發症，目前對於bortezomib 造成神經痛的基本機制並不清楚。這一研究計畫的目的是探討bortezomib 神經病變造成疼痛的機制。我們推測脊髓背角於此一神經痛扮演關鍵的角色，特別是表觀遺傳調控 (epigeneticregulations) 如何影響疼痛分子的基因表達 (gene expression)。表觀遺傳調控影響多種神經功能，但是在疼痛領域的研究並不多見，特別是脊髓背角對於疼痛的影響。研究計畫將以bortezomib 神經病變的動物模式，探討一重要的表顯遺傳調控因子，即組蛋白去乙醯酶 (histone deacetylase) 對於脊髓背角導致疼痛的調控機制，作為發展可能治療策略的基礎。第一年將建立bortezomib 大鼠與小鼠動物模式，並以免疫化學染色與西方墨點分析組蛋白去乙醯酶在脊髓背角之表達。第二年將依據第一年的研究結果，選定基因表達有增加的組蛋白去乙醯酶作為標的，驗證組蛋白去乙醯酶的對於bortezomib 神經痛之效應：將以不同的組蛋白去乙醯酶之藥理抑制劑 (pharmacological inhibitors) 分析，以瞭解那些特殊亞型的組蛋白去乙醯酶對於神經痛最有影響。第三年將以 RNA 干擾 (RNAi)之方法抑制特定亞型之組蛋白去乙醯酶，檢查 (1)組蛋白去乙醯酶對於疼痛行為以及 (2)受組蛋白去乙醯酶調控之下游疼痛相關分子的影響。預期這些研究結果將對於化學治療引起的神經病變與神經痛提供新的見解與治療方向。<br> Abstract: Chemotherapy-induced neuropathy is an important etiology of sensory nerve disorders and target therapyhas become novel strategies for treatment of malignant diseases, for example, bortezomib. Sensorysymptoms including neuropathic pain are major complications of bortezomib neuropathy. The dorsal hornof the spinal cord plays a key role in the pathogenesis of neuropathic pain which transmits peripheralafferents into central sensitization. The molecular mechanisms, in particular, the modulations of geneexpressions underlying neuropathic pain at the spinal cord level is not completely understood. Epigeneticregulations are one of the important mechanisms modulating gene expression. There were, however, onlylimited studies to explore the influences of epigenetic regulations on neuropathic pain mechanisms, let alonebortezomib neuropathy. This proposal aims to examine molecular mechanisms of neuropathic pain inbortezomib neuropathy at the spinal cord level. We will first generate models of bortezomib neuropathy andthen explore the influences of epigenetic regulations on molecular mediators in bortezomib-inducedneuropathic pain. Specifically, we will focus on the role of histone acetylase on gene expression in thedorsal horn and the downstream molecular mediators of neuropathic pain. During year 1, we will set upbortezomib neuropathy model in rats and mice and examine the expression patterns of histone deacetylasesin the dorsal horn. In year 2, this proposal will investigate the effects of histone acetylase with acombination of pharmacological inhitors to delineate specific types of histone deacetylases which will beresponsible for pain in bortezomib neuropathy. This proposal will also examine interacting proteins toexplore molecular mediators of pain related to histone deacetylase. During Year 3, we will silence thespecific subtypes of histone acetylase according to pharmacological inhibition experiments and investigatethe effects of knockdown on (1) neuropathic pain behaviors and (2) downstream pain molecules regulatedby histone deacetylase in bortezomib neuropathy. The results will provide new insights on therapeuticdirections of neuropathic pain in bortezomib neuropathy.化學治療神經病變神經痛表觀遺傳學基因表達chemotherapypolyneuropathyneuropahic painepigenetic regulationgene expression