臺灣博碩士論文加值系統

子宮內膜異位症是子宮內膜組織不正常生長在子宮腔以外的地方，為一種常見的婦科疾病，生育年齡婦女的盛行率大約是百分之十，在臨床上的主要症狀為慢性骨盆腔疼痛、經痛以及不孕，進而降低患者的生活品質。然而，子宮內膜異位症的致病機制極為複雜且尚未清楚，目前最被接受的原因為經血逆流學說，當月經來潮時，子宮內膜組織經由輸卵管逆流至骨盆腔進而附著生長。在實驗室先前的研究中發現，異位的子宮內膜基質細胞表現大量的缺氧誘導因子-1α，基於逆流學說可能造成逆流的子宮內膜細胞面臨缺氧的情況，同時缺氧被認為是導致許多病理過程的關鍵因素。因此，本研究的主要目標為探討缺氧誘導的病理改變可能導致子宮內膜異位症發展的原因，同時進一步探討以缺氧誘導的病理改變作為標的，進行非賀爾蒙治療的可能性。研究的結果顯示，調控細胞醣類代謝主要的酵素丙酮酸脫氫酶激酶-1在子宮內膜異位基質細胞中大量表現，而缺氧的確可以藉由轉錄調控而促進丙酮酸脫氫酶激酶-1表現。相較於子宮內膜原位基質細胞，高度表現丙酮酸脫氫酶激酶-1的異位基質細胞伴隨著較多的乳酸產生以及較高耗氧速率，而乳酸產生和細胞耗氧速率在給予丙酮酸脫氫酶激酶抑制劑（dichloroacetate）的處理下會減少。此外，缺氧所誘導的丙酮酸脫氫酶激酶-1能夠幫助子宮內膜基質細胞克服過氧化氫以及低營養環境所引起的細胞死亡。另一方面，生物資訊的分析結果顯示，神經營養性酪氨酸激酶2型受體可能做為藥物治療的標的。同時，實驗結果顯示神經營養性酪氨酸激酶2型受體在子宮內膜異位症的臨床檢體以及子宮內膜異位症模擬老鼠的組織中大量表現，而且細胞實驗結果證明了缺氧能夠透過缺氧誘導因子-1α促進神經營養性酪氨酸激酶2型受體在子宮內膜基質細胞中表現。在實驗中，利用神經營養性酪氨酸激酶2型受體的小分子非競爭性拮抗劑（ANA-12）處理子宮內膜異位基質細胞，則能造成異位細胞的死亡。進一步給予子宮內膜異位症模擬老鼠ANA-12的處理，發現異位病灶體積有減小的情況，因此認為ANA-12有潛力作為子宮內膜異位症治療的藥物。總結研究結果推斷，缺氧誘導的病理改變參與在子宮內膜異位症的發展過程中，而針對缺氧誘導的病理改變作為目標有可能進一步發展成為治療子宮內膜異位症的方法。

Endometriosis is a common gynecological disease, which affects about 10% of women in reproductive-age. It causes chronic pelvic pain, dysmenorrhea and infertility and decreases the life quality of patients. However, the cause of endometriosis is complex and largely unclear. Our previous study demonstrates that HIF-1α is up-regulated in ectopic endometriotic stromal cells. Since hypoxia is a critical factor leading to many pathological processes, thus the overall objective of this study is to investigate hypoxia-induced pathological alteration that may contribute to the progression of endometriosis, and to further explore the potential hormone-independent treatments base on the hypoxia-induced pathological alteration. Here, we found the expression of pyruvate dehydrogenase kinase 1 (PDK1), a critical enzyme in regulating glucose metabolism, was increased in ectopic stromal cell. Molecular characterization reveals that overexpression of PDK1 is induced by hypoxia through transcriptional regulation. Upregulation of PDK1 in ectopic endometriotic stromal cells is accompanied by increases in lactate production and oxygen consumption rate as compared to eutopic endometrial stromal cells. Furthermore, our data show that lactate production and oxygen consumption rate of ectopic stromal cells were decreased when cells were treated with PDK1 inhibitor, dichloroacetate. In addition, hypoxia-induced PDK1 expression prevents cells from H2O2- and low nutrient-induced cell death. On the other hand, we performed the bioinformatics analysis and found neurotrophic receptor tyrosine kinase 2 (NTRK2, also known as TrkB) as a potential candidate for treatment. Both in clinical specimen and the endometriosis mouse model, the levels of NTRK2 were markedly upregulated in the lesions. In addition, we found that hypoxia can induce NTRK2 expression in a HIF1α-dependent manner. Administration of ANA-12, a selective non-competitive antagonist of NTRK2, significantly induced endometriotic stromal cells death, suggesting it may be a potential therapeutic agent. Indeed, treatment of endometriotic lesion-bearing mice with ANA-12 (1.5 mg/kg body weight) caused the ectopic lesions regression. Taken together, our results demonstrate that hypoxia-induced pathological alterations involve in the progression of endometriosis, which can be the target of treatment for endometriosis.

Contents
摘要 I
Abstract III
誌謝 V
Abbreviation XI
Overview of endometriosis and hypoxia 1
Endometriosis 1
Theories of pathogenesis 1
Treatments 3
Mechanisms of development of endometriosis 6
Hypoxia 7
Objective and aims 11
PDK1 in endometriosis 13
Introduction 13
Materials and Methods 14
Results 19
Discussion 22
NTRK2 in endometriosis 26
Introduction 26
Materials and methods 27
Results 31
Discussion 34
Conclusion 36
References 38
Figures 53
Tables 80
Publications 85

Table contents
Table 1. Reagents and instruments 80
Table 2. Primer sequences 83
Table 3. Antibody list 84

Figure contents
Figure 1. Schematic drawings show domain structure and regulation of HIFs. 53
Figure 2. Hypoxia is involved in pathological processes of endometriosis. 54
Figure 3. The typical characteristics of the Warburg-effect in endometrial and endometriotic stromal cells. 55
Figure 4. The oxygen consumption rates are measured in the endometrial and endometriotic stromal cells. 56
Figure 5. The intercellular ATP content and mitochondrial membrane potential are measured in the eutopic and ectopic stromal cells. 57
Figure 6. The mRNA levels of PDK1 and PDK3 are elevated in endometriotic ectopic stromal cells. 58
Figure 7. The protein level of PDK1 is upregulated in endometriotic ectopic stromal cells. 59
Figure 8. PDK1 is induced by hypoxia. 60
Figure 9. Hypoxia mediates PDK1 induction via transcriptional regulation. 61
Figure 10. Representative Western blot of the DCA treated and the shRNA treated ectopic cells. 62
Figure 11. Upregulated PDK1 regulates lactate production of ectopic endometriotic stromal cells. 63
Figure 12. Glucose uptake ability of ectopic cell is not altered by DCA treatment. 64
Figure 13. Upregulated PDK1 is involved in oxygen consumption of ectopic endometriotic stromal cell. 65
Figure 14. DCA attenuates anti-apoptotic ability of ectopic stromal cells. 66
Figure 15. Blocking the PDK activity attenuates antiapoptotic ability of hypoxia pre-treated eutopic stromal cells. 67
Figure 16. NTRK2 expression level is elevated in three public datasets. 68
Figure 17. NTRK2 expression level is elevated in ectopic tissues. 69
Figure 18. The elevated level of NTRK2 is menstrual cycle independent. 70
Figure 19. Expression level of NTRK2 and BDNF are increased in ectopic endometriotic stromal cells. 71
Figure 20. Cytokine stimuli do not induce the mRNA expression of NTRK2. 72
Figure 21. The NTRK2 induction is mediated by hypoxia. 73
Figure 22. Elevated NTRK2 expression promotes ectopic stromal cell growth. 74
Figure 23. Blocking NTRK2 decreases the viability of ectopic stromal cells. 75
Figure 24. Surgical-induced endometriosis in mice. 76
Figure 25. Specific NTRK2 inhibitor decreases the lesion growth in the endometriosis mouse model. 77
Figure 26. PDK1 and NTRK2 may not affect each other. 78
Figure 27. Hypoxia-induced PDK1 and NTRK2 in the pathogenesis of endometriosis. 79
 

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