臺灣博碩士論文加值系統

第一部分：
1.Fibronectin間質形成與細胞附著、移動及分化有關。但到目前為止，它的調節機轉仍未明朗。根據之前的研究報告指出，integrin與之有關。在本篇論文裡，則將探索protein kinase在fibronectin 間質形成中所扮演的角色，我們以免疫螢光染色的方法來定量分析Xenopus 細胞培養之纖維母細胞聚合fibronectin的情形。
2.於細胞培養中直接加入soluble fibronectin (30μg/ml)，可觀察到纖維母細胞將其轉化為固著的形式，且此一現象隨時間延長會有增加的趨勢，處理二天後，有些fibronectin間質形成於纖維母細胞之外。
3.前處理RGDS (50μg/ml)、 Rhodostomin (10μg/ml)、genistein (50μM)、cytochalasin D (1μM)、H-7 (10μM)、Ro-31-8220 (3μM)及forskolin (10μM)時，fibronectin的聚合作用明顯受到抑制。
4.當細胞共同處理fibronectin及TPA一小時，可明顯地加強fibronectin網狀結構的形成。
5.TPA促進Integrin及vinculin的clustering，而forskolin抑制之。
6.和soluble fibronectin培養一天後，將細胞以前述之抑制劑(Rhodostomin、genistein、cytochalasin D、H-7及forskolin)處理30分鐘，發現除Rhodostomin外，其餘藥物皆可有效的分解fibronectin的網狀結構。這顯示fibronectin間質形成是屬於動態變化的行為，且會受到protein kinase的調節。但已形成之fibronectin間質，則短時間內較不受disintegrin的影響。
7.Aprotinin (1μg/ml)、leupeptin (1μg/ml)及低濃度的matrix metalloproteinase inhibitor 1 (2μM)，會拮抗forskolin的fibronectin網狀結構之分解作用，但genistein、cytochalasin D、H-7、Ro-31-8220的作用則不受影響。若給予高濃度的matrix metalloproteinase inhibitor 1 (150μM)，則上述藥物的fibrillar fibronectin之分解作用均被拮抗。
8.總結此篇論文可得：fibronectin間質組成乃是動態的，其聚合與integrin有關。細胞骨架的重組、tyrosine kinase及serine-thereonine kinase均會調節此一作用。其中Protein kinase C 加強而protein kinase A會抑制fibronectin的聚合。
第二部分：
1.許多由荷爾蒙控制之生理反應，諸如分泌、基因表現及細胞增殖都經過第二訊息傳遞物─cAMP所調節。但即使cAMP是最先被證實和荷爾蒙作用有關之物質，其詳細機轉及過程中所受到的外在影響至今仍然未完全了解。
2.Fibronectin、laminin及collagen是細胞間質(Extracellular matrix；ECM)的成員，對於細胞的附著、遷徙、分化及增生皆扮演重要的角色。本實驗室先前的實驗發現，fibronectin及laminin可影響PKC或PKA的訊息傳遞路徑進而調節胚胎期運動神經自發性乙醯膽鹼(ACh)之釋放。因此本論文就以間質蛋白對PKA的作用為題，針對其調節胚胎期運動神經ACh的釋放之可能結果進行探討。
3.於一天大的爪蟾胚胎神經-肌細胞培養，在有神經支配的肌細胞上形成whole-cell recording (Vh=-60~-65mV)，可記錄到自發性ACh所引起的微終板電流(spontaneous synaptic currents；SSCs)，我們可以藉由記錄這樣的SSC頻率來研究胚胎期運動神經的活性。
4.Forskolin是adenylate cyclase的活化劑。培養在塗抹了fibronectin玻片的細胞於加入20μM forskolin後，其SSC頻率明顯地增加，然而，培養在塗抹laminin或collagen玻片的細胞於加入forskolin後，其SSC 頻率並無有意義的變化。
5.DBcAMP (1mM)是PKA的活化劑。同樣地只有加入培養在fibronectin-coated玻片的細胞，才可促使SSC頻率增加；而培養在laminin-coated或collagen-coated玻片的細胞則沒有影響。
6.將CGRP (3μM)直接加入培養在fibronectin-coated玻片的細胞，並不能改變自發性ACh釋放的頻率。
7.Isoproterenol是非選擇性的βagonist。培養在塗抹了fibronectin玻片的細胞於加入10μM Isoproterenol後，可觀察到SSC頻率明顯地增加，然而，培養在塗抹laminin、collagen玻片的細胞在加入isoproterenol後，其SSC 頻率並無有意義地增加。
8.Albuterol是選擇性的β2 agonist，一如前者，加入10μM Albuterol只可調節培養在fibronectin-coated玻片的細胞之SSC頻率。
9.將細胞培養在沒有塗抹任何間質的玻片，單獨給予isoproterenol (10μM)或soluble fibronectin (6μg/ml)並不能影響自發性ACh釋放的頻率，但若在給予isoproterenol (10μM)後十分鐘給予soluble fibronectin，則會使ACh自發性釋放增加。
10.將細胞培養在fibronectin-coated玻片上，於四小時後加入神經滋養因子再培養一天，而後觀察DBcAMP及isoproterenol對其自發性ACh釋放頻率之影響。發現BDNF可抑制DBcAMP所引發的 SSC增加，CNTF、GDNF及NT-3則反而會促進之。
11.總結此篇論文可知，fibronectin能影響β receptor的傳遞途徑，進而促使PKA的活化。故可由此而調節胚胎期運動神經自發性ACh之釋放，改變神經的活性。

Part I：
1.The assembly of fibronectin matrix is a key event in regulating cell adhesion, migration, and differentiation. The signal transduction pathway that regulates fibronectin assembly is still unclear. To elucidate the regulatory role of protein kinase in the formation of fibronectin matrix, we quantitatively examined the fibronectin assembly by fibroblast in Xenopus cell cultures using fluorescent immunocytochemistry.
2.Soluble form of bovine fibronectin was bath-applied to the cultures. Fibroblast changed the soluble form of fibronectin into immobilized form time-dependently.
3.Treatment with RGDS, Rhodostomin, genistein, cytochalasin D, H-7, Ro-31-8220 and forskolin inhibited the assembly of immobilized fibronectin.
4.When the fibronectin assembly was shortened to 1 hr, co-incubation with TPA significantly enhanced the formation of immobilized fibronectin.
5.The clustering of integrin and integrin were enhanced and inhibited by TPA and forskolin, respectively.
6.After one day’s incubation with soluble fibronectin to form immobilized fibronectin network, treatment with genistein, cytochalasin D, H-7 or forskolin for 30 min degraded the fibronectin networks, indicating that fibronectin fibrillogenesis is dynamic and modulated by protein kinases.
7.Aprotinin, leupeptin and matrix metalloproteinase inhibitor 1 (2μM) selectively antagonized the fibronectin matrix degradative action of forskolin, but not that caused by genistein, cytochalasin D and H-7. On the other hand, the higher concentration of matrix metalloproteinase inhibitor 1 (150μM) antagonized the fibronectin matrix degradative action caused by all these drugs.
8.These results suggest that the formation of fibronectin matrix beneath the fibronblast is dynamic. Cytoskeleton organization, tyrosine kinase and serine-threonine kinases are all involved in the regulation of fibronectin fibrillogenesis. Protein kinase C potentiates and protein kinase A inhibits the assembly of fibronectin matrix.
Part II：
1.Numerous processes including secretion, gene expression and proliferation are controlled by hormones which act through the second messenger cAMP. Although cAMP was the first discovered second messenger of hormone action, much remains to be learned about its mode of action and the regulation of signaling pathways which utilize this second messenger.
2.Extracellular matrix (ECM) proteins such as fibronectin, laminin and collagen have been implicated in a wide variety of cellular properties which include cell adhesion, migration, differentiation and proliferation. The previous data of our laboratory showed that fibronectin and laminin markedly increased spontaneous ACh release via increasing PKA or PKC activity. The aim of the present study is to further analyze the modulation of protein kinase A activity in synaptic transmission by matrix proteins at developing motoneurons.
3.The cultures of spinal neurons and myotomal cells were prepared from 1-day-old Xenopus embryos. Spontaneous synaptic currents (SSCs) were recorded from innervated myocytes of natural synapses by whole-cell voltage-clamped recordings (Vh=-60~-65 mV).
4.Bath application of an adenylate cyclase activator forskolin (20 μM) resulted in significant enhancement of the SSC frequency in cultures grown on fibronectin substratum but not on laminin- or collagen-coated glass.
5.Bath application of a PKA activator DBcAMP (1mM) resulted in significant enhancement of the SSC frequency in cultures grown on fibronectin substratum but not on laminin- or collagen-coated glass.
6.Application of 3μM CGRP did not significantly affect the spontaneous ACh release in cultures grown on fibronectin substratum.
7.Bath application of a non-selective β agonist isoproterenol (10μM) resulted in significant enhancement of the SSC frequency in cultures grown on fibronectin substratum but not on laminin- or collagen-coated glass.
8.Bath application of a selective β2 agonist albuterol (10μM) resulted in significant enhancement of the SSC frequency in cultures grown on fibronectin substratum but not on laminin- or collagen-coated glass.
9.When cells were cultured on non-coated glasses, application of isoproterenol (10μM) or soluble fibronectin (6μg/ml) alone did not significantly affect the spontaneous ACh release. However, sequential application of soluble fibronectin and isoproterenol markedly increased the SSC frequency.
10.Bath application of BDNF (30 ng/ml), CNTF (150 ng/ml), GDNF (30 ng/ml) or NT-3 (50 ng/ml) was bath applied to 4 hr‘s cultures grown on fibronectin-coated glasses. After one day’s incubation, BDNF inhibited but CNTF, GDNF and NT-3 potentiated SSC enhancement in response to addition to DBcAMP.
11.In summary, these results suggest that fibronectin matrix protein potentiates the activation of PKA and may play an important role in regulating synaptic transmission at developing motoneuron.

目 錄
第一部分
中文摘要1
英文摘要3
緒論5
實驗材料與方法14
結果18
討論64
第二部分
中文摘要69
英文摘要72
緒論74
實驗材料與方法82
結果85
討論120
參考文獻128

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