因為創傷或者疾病對周邊神經的損害會造成神經病變，並引發許多症狀，包括劇烈的疼痛，肌肉衰弱，麻痺或者器官機能失調等。導致神經病變最常見的原因與代謝失調相關，特別是糖尿病。很多糖尿病患者，尤其是血糖控制不當的一些病例，初期會影響周邊神經的末端，造成對稱性的神經痛，而且會逐漸擴散到接近中樞神經的近端。過去許多研究顯示，糖尿病所引起的神經病變與神經滋養因子的缺乏息息相關。最近一些研究發現，藉由在周邊神經進行血管內皮細胞增長因子、親神經滋養因子-3、神經生長因子，腦衍生神經滋養因子或者肝細胞生長因子等神經滋養因子的基因傳送，可以使神經營養因子持續產生並且減輕糖尿病所衍生的神經病變。然而另外一個重要的神經滋養因子，膠質細胞源性神經營養因子在糖尿病衍生的神經病變所扮演的角色則尚未被證實。因此這個研究計畫的目的主要是探討在大鼠的坐骨神經所支配的肌肉周圍進行膠質細胞源性神經營養因子基因傳送對於高血糖症或者緊迫所引起之神經損傷是否具有保護效應。首先，我們要探討在坐骨神經損傷期間組織的改變以及膠質細胞源性神經營養因子與其訊息傳遞路徑相關的接受器表現量的變化。接著，評估腺病毒載體在坐骨神經所支配的肌肉周圍進行膠質細胞源性神經營養因子基因傳送對於防止神經退化的可行性，並且研究其改善神經病變的分子機制。預期上述研究結果能夠幫助我們釐清在周邊神經傳送膠質細胞源性神經營養因子重組基因載體，是否可以作為治療糖尿病衍生神經病變或其他周邊神經病變的合適策略，並進一步作為將來臨床運用之基礎。

Damage to peripheral nerves following trauma or disease has a number of consequences including burning pain, muscle wasting, paralysis, or organ dysfunction. The most common form of neuropathy is that associated with metabolic abnormality, notably diabetes. Many diabetics, especially those with poor blood sugar control, ultimately develop a distal symmetrical and painful neuropathy that initially affects the longest peripheral axons, but with time spreads proximally. Deficiency in neurotrophic support has been proposed to contribute to the development of diabetic neuropathy. Recently, peripheral gene delivery of vascular endothelial growth factor (VEGF), neurotrophin-3 (NT-3), NGF, BDNF or hepatocyte growth factor (HGF) has been shown to facilitate the continuous production of neurotrophic factors and alleviate the diabetic neuropathy. The role of glial cell-derived neurotrophic factor (GDNF) in the pathogenesis and therapeutics of diabetic neuropathy is not well defined. The main objectives of this research sought to inspect the protective effect of GDNF peripheral gene delivery during hyperglycemia- or constriction- induced sciatic nerve injury in rats. In present proposal, we propose to investigate the change in organization and expressions of GDNF signaling complex in the sciatic nerve following injury in the initial stage. Subsequently, the recombinant adenovirus was used gene delivery system for GDNF to evaluate the potential of intramuscular administration of gene delivery for prevent nerve degeneration, and the molecular mechanism of GDNF to ameliorate neuropathy will be clarified. The above study would enable us to test the hypothesis that the topical gene delivery might be a suitable strategy for the treatment of diabetic neuropathy and other disorders in peripheral nerve. Furthermore, the results of animal studies might be extrapolated for future clinical application.

Index
Abstract in Chinese……………………….....……………. i
Abstract in English………………………………………... iii
Chapter1
Peripheral Gene Transfer of Glial Cell-Derived Neurotrophic Factor Ameliorates the Neuropathic Deficits in Diabetic Rats………………………...…….………………. 1
ABSTRACT………………………………….……………...…. 2
INTRODUCTION………………………………….………….. 3
MATERIALS AND METHODS………………………………..............…………. 5
RESULTS………………………………….…….…………. 11
DISCUSSION……………………………..……………….. 18
TABLE, FIGURES AND LEGENDS……...………..…….. 23
Chapter 2
Glial Cell Line-Derived Neurotrophic Factor Gene Transfer Exerts Protective Effect on Axons in Sciatic Nerve Following Constriction-Induced Peripheral Nerve Injury……......... 36
ABSTRACT…………………………………………………. 37
INTRODUCTION……………………………….…......…… 38
MATERIALS AND METHODS……………………..……… 40
RESULTS…………………………………………….…….. 44
DISCUSSION………………………………………....……. 50
FIGURES AND LEGENDS………………………...……… 54
CONCLUSION……………………………………..………. 64
REFERENCES……………………………………….……. 65
PUBLICATION LIST………………………………….…..... 75

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