根據先前的研究，運動會刺激骨骼肌肉膜蛋白 (Fibronectin type III domain-containing protein 5； FNDC5)大量表現，FNDC5裂解後以Irisin 型式分泌， 而進一步產生作用；此外若將 Irisin Arg-75胺基酸點突變為Glutamine，產生之 IrisinR75E突變將會導致 Irisin雙體結構的形成及功能受影響。雖然Irisin在脂肪棕化、體內濃度異常時會與許多慢性疾病有關、促進脂肪的分解並降低胰島素阻抗性的現象、促進成骨細胞的增生與分化、甚至是調節肌肉-脂肪-骨骼-神經元之間的連接者等研究已有許多文獻報導，然而Irisin對於胚胎發育早期運動神經生長方向是否具有導引作用則是到目前還是不清楚。
探討Irisin在胚胎發育時期造成神經生長錐偏轉現象(growth cone turning)以及其訊息傳遞路徑。我們以非洲爪蟾(Xenopus Laevis)的神經培養，利用turning assay的實驗方式來探討Irisin對神經生長錐生長呈現趨向或逆向的偏轉。使用培養後4至10小時的神經細胞，注射用玻璃毛細管(直徑約 1-1.2 μm)以每秒1次，每次50 msec duration的給藥方式來進行實驗。
研究結果顯示在投與Irisin情況下，能誘導神經生長錐的偏轉但不會增加神經生長錐的生長速度而IrisinR75E則是不論對神經生長的速度或是方向均沒有影響.。在鈣離子儲存池的排空劑Thapsigargin及IP3 receptor抑制劑XeC預處理後的結果顯示Irisin均無法誘導神經生長錐的偏轉。分別使用PLCγ抑制劑U73122、PI3K抑制劑Wortmannin、tyrosine kinase receptor抑制劑Genistein， 都能有效抑制Irisin所造成的生長錐的偏轉現象。由於細胞內鈣離子因store depletion後會促使細胞膜上TRPC channel(store-operated Ca2+ channel)的打開，使得細胞外鈣離子流入細胞內；我們使用Ca2+-free Ringer medium及TRPC channel抑制劑SKF96365後，結果均顯示Irisin無法誘導神經生長錐的偏轉。使用CaMK II抑制劑KN62可以有效抑制Irisin對神經生長的吸引作用。Irisin的神經生長引導作用會被前處理AMPK的抑制劑Compound C所抑制，為了確定AMPK角色，我們改直接投與AMPK的促進劑Metformin，結果顯示在Metformin的作用下能產生與irisin一樣的誘導神經生長錐的偏轉，以上結果顯示Irisin可以引發細胞內鈣離子store depletion後使得TRPC channel的打開後讓細胞外離子流入細胞內，流入的calcium與calmodulin形成complex之後進一步促使CaMK II的活化，CaMK II的活化進而促使AMPK的活化而造成神經生長錐的偏轉。而神經生長錐的偏轉與Rho GTPase family中的Cdc42及Rac1息息相關，為了確定AMPK與而Cdc42及Rac1的關係，最後我們使用Cdc42抑制劑ML141及Rac1抑制劑NSC23766，結果均顯示在此兩種抑制劑的存在之下Irisin無法誘導神經生長錐的偏轉，綜合上面結果顯示，Irisin與細胞膜上的tyrosine kinase receptor作用後，經PI3K pathway活化PLCγ使得IP3能作用在IP3 receptor後排空鈣離子儲存池中的鈣離子，再藉由TRPC channel讓細胞外鈣離子流入與calmodulin形成complex促使CaMK II的活化，CaMK II的活化進而促使AMPK的活化來影響Rho GTPase family中的Cdc42及Rac1的活性，進而影響神經生長錐的偏轉。

Irisin, the cleaved fragment of the transmembrane protein fibronectin type-III domain containing protein 5 (FNDC5), is an exercise-induced myokine that is involved in the regulation of adipose browning and thermogenesis. Recent studies have uncovered some important biological functions of irisin in nervous system. For example, irisin regulates depressive-like behavior, induces neural differentiation of embryonic stem cell and protects against oxygen-glucose-induced neuronal injury. In this study, we focused on the possibility and underlying molecular mechanisms of irisin in the axonal guidance by using developing motoneurons of Xenopus laevis. The chemical gradient of irisin on a growth cone can be achieved through pressure-derived irisin ejection from a micropipette at 1 Hz in frequency, 50 msec in duration. Although the growth rate of developing axons was not significantly affected, irisin elicited a significant attraction on the growth cone. Neither growth rate nor direction of the growth cone was affected in the presence of irisinR75E, a glutamate substitution in the functional domain of irisin. The irisin-induced attractive axonal guidance was abolished in the presence of sarcoplasmic reticulum calcium ATPase inhibitor thapsigargin, suggesting an release of calcium ions (Ca2+) from intracellular Ca2+ store is responsible for irisin-induced turning response. Pretreatment of IP3 receptor inhibitor (XeC) but not ryanodine receptor inhibitors (ruthenium red, TMB-8) effectively occluded growth cone turning response induced by irisin. Furthermore, the irisin-induced attractive truning response on the growth cone is effectively hampered in the presence of either PLCγ inhibitor U73122, PI3 kinase inhibitor wortmannin or tyrosine kinase receptor inhibitor genistein. The irisin-induced attractive guidance effect was abolished when Ca2+ was eliminated from the culture medium or TRPC channel inhibitor SKF96365, suggesting an internal store depletion-induced influx of Ca2+ is responsible for irisin-induced turning response. Bath application of CaMK II inhibitor (KN62) effectively occluded growth cone turning response induced by irisin. Microinjection of AMPK activator metformin mimic irisin-induced turning response and bath application of AMPK inhibitor compound C significantly abolished irisin-induced attractive axonal guidance. Moreover, retreatment inhibitors of monomergic G protein Rac1 and Cdc42 significantly hampered the axonal guidance effect of irisin. AMPK activation may affect the activity of Rac1 and Cdc42 (Rho GTPase family), thereby affecting the nerve growth cone turning. Overall, our results suggest through IP3-induced internal Ca2+ depletion, irisin elicits TRPC-CAM kinase-AMPK signaling cascade which result in the attractive axonal guidance at developing motoneuron.

論文審定書……………………………………………………………….i
致謝………………………………………………………………………....ii
中文摘要………………………………………………………………...iii
Abstract…………………………………………………………………..v
目錄…………………………………………………………………….....vii
圖目錄……………………………………………………………………viii
附圖目錄………………………………………………………………….x
縮寫表…………………………………………………………………....xi
緒論………………………………………………………………………....1
實驗目的………………………………………………………………..12
實驗材料………………………………………………………………..13
實驗方法………………………………………………………………..16
結果…………………………………………………………………….....19
討論…………………………………………………………………….....31
參考文獻………………………………………………………………..35

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