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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
| dc.contributor.author | Yu-Jhen Yu | en |
| dc.contributor.author | 余昱臻 | zh_TW |
| dc.date.accessioned | 2021-07-11T14:48:48Z | - |
| dc.date.available | 2025-08-11 | |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-11 | |
| dc.identifier.citation | Ambizas EM, Ginzburg R. 2007. Lubiprostone: a chloride channel activator for treatment of chronic constipation. Ann Pharmacother 41: 957-964. Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W et al. 2013. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 45: 1055-1060. Bassett MH, White PC, Rainey WE. 2004. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 217: 67-74. Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E et al. 2013. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 45: 440-444, 444e441-442. Bi MM, Hong S, Zhou HY, Wang HW, Wang LN, Zheng YJ. 2013. Chloride channelopathies of ClC-2. Int J Mol Sci 15: 218-249. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, Jentsch TJ. 2007. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 27: 6581-6589. Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ. 2001. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption. EMBO J 20: 1289-1299. Boulkroun S, Fernandes-Rosa FL, Zennaro MC. 2020. Old and new genes in primary aldosteronism. Best Pract Res Clin Endocrinol Metab 34: 101375. Clark BJ, Pezzi V, Stocco DM, Rainey WE. 1995. The steroidogenic acute regulatory protein is induced by angiotensin II and K+ in H295R adrenocortical cells. Molecular and Cellular Endocrinology 115: 215-219. Clyne CD, Zhang Y, Slutsker L, Mathis JM, White PC, Rainey WE. 1997. Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Mol Endocrinol 11: 638-649. Cuppoletti J, Blikslager AT, Chakrabarti J, Nighot PK, Malinowska DH. 2012. Contrasting effects of linaclotide and lubiprostone on restitution of epithelial cell barrier properties and cellular homeostasis after exposure to cell stressors. BMC Pharmacol 12: 3. Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, Jeunemaitre X, Boulkroun S, Amar L, Strom TM et al. 2016. CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism. EBioMedicine 13: 225-236. Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, van Berkel C, Polder E, Tollard E, Darios F et al. 2013. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. The Lancet Neurology 12: 659-668. Di Bella D, Pareyson D, Savoiardo M, Farina L, Ciano C, Caldarazzo S, Sagnelli A, Bonato S, Nava S, Bresolin N et al. 2014. Subclinical leukodystrophy and infertility in a man with a novel homozygous CLCN2 mutation. Neurology 83: 1217-1218. El Ghorayeb N, Bourdeau I, Lacroix A. 2016. Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism. Front Endocrinol (Lausanne) 7: 72. Fernandes-Rosa FL, Boulkroun S, Zennaro MC. 2017. Somatic and inherited mutations in primary aldosteronism. J Mol Endocrinol 59: R47-R63. -. 2020. Genetic and Genomic Mechanisms of Primary Aldosteronism. Trends Mol Med. Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H et al. 2018. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nature Genetics 50: 355-361. Goppner C, Orozco IJ, Hoegg-Beiler MB, Soria AH, Hubner CA, Fernandes-Rosa FL, Boulkroun S, Zennaro MC, Jentsch TJ. 2019. Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism. Nat Commun 10: 4678. Harvey A, Friend EJ. 2014. Adrenal gland. in Feline Soft Tissue and General Surgery, pp. 393-399. Hattangady NG, Olala LO, Bollag WB, Rainey WE. 2012. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350: 151-162. Hu X, Tang Z, Li Y, Liu W, Zhang S, Wang B, Tian Y, Zhao Y, Ran H, Liu W et al. 2015. Deletion of the tyrosine phosphatase Shp2 in Sertoli cells causes infertility in mice. Sci Rep 5: 12982. Hu YJ, Wang YD, Tan FQ, Yang WX. 2013. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep 40: 6123-6142. Jansen PM, Hofland J, van den Meiracker AH, de Jong FH, Danser AH. 2012. Renin and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15. J Renin Angiotensin Aldosterone Syst 13: 360-366. Jentsch TJ, Friedrich T, Schriever A, Yamada H. 1999. The CLC chloride channel family. Pflugers Arch 437: 783-795. Jeworutzki E, Lopez-Hernandez T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Muller CS, Schulte U et al. 2012. GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron 73: 951-961. Jin Y, Blikslager AT. 2015. ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target. Tissue Barriers 3: e1105906. Jin Y, Pridgen TA, Blikslager AT. 2015. Pharmaceutical Activation or Genetic Absence of ClC-2 Alters Tight Junctions During Experimental Colitis. Inflamm Bowel Dis 21: 2747-2757. Korah HE, Scholl UI. 2015. An Update on Familial Hyperaldosteronism. Horm Metab Res 47: 941-946. Li LA, Chang YC, Wang CJ, Tsai FY, Jong SB, Chung BC. 2004a. Steroidogenic factor 1 differentially regulates basal and inducible steroidogenic gene expression and steroid synthesis in human adrenocortical H295R cells. J Steroid Biochem Mol Biol 91: 11-20. Li LA, Wang PW, Chang LW. 2004b. Polychlorinated biphenyl 126 stimulates basal and inducible aldosterone biosynthesis of human adrenocortical H295R cells. Toxicol Appl Pharmacol 195: 92-102. Liang GH, Weber CR. 2014. Molecular aspects of tight junction barrier function. Curr Opin Pharmacol 19: 84-89. Lin CW, Chang YH, Pu HF. 2012. Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. Toxicology 298: 14-23. Liu C, Zhang X, Chang H, Jones P, Wiseman S, Naile J, Hecker M, Giesy JP, Zhou B. 2010. Effects of fluorotelomer alcohol 8:2 FTOH on steroidogenesis in H295R cells: targeting the cAMP signalling cascade. Toxicol Appl Pharmacol 247: 222-228. Lui WY, Cheng CY. 2007. Regulation of cell junction dynamics by cytokines in the testis: a molecular and biochemical perspective. Cytokine Growth Factor Rev 18: 299-311. Mete O, Duan K. 2018. The Many Faces of Primary Aldosteronism and Cushing Syndrome: A Reflection of Adrenocortical Tumor Heterogeneity. Front Med (Lausanne) 5: 54. Miller WL. 2007. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771: 663-676. Moeser AJ, Nighot PK, Engelke KJ, Ueno R, Blikslager AT. 2007. Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC-2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol 292: G647-656. Mok KW, Mruk DD, Cheng CY. 2013. Regulation of Blood–Testis Barrier (BTB) Dynamics during Spermatogenesis via the “Yin” and “Yang” Effects of Mammalian Target of Rapamycin Complex 1 (mTORC1) and mTORC2. pp. 291-358. Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA, Rabbia F et al. 2017. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol 69: 1811-1820. Moraitis AG, Rainey WE, Auchus RJ. 2013. Gene mutations that promote adrenal aldosterone production, sodium retention, and hypertension. Appl Clin Genet 7: 1-13. Mruk DD, Cheng CY. 2004. Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 25: 747-806. -. 2011. An in vitro system to study Sertoli cell blood-testis barrier dynamics. Methods Mol Biol 763: 237-252. Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, Fischer E, Tizzani D, Pallauf A, Viola A et al. 2012. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 59: 235-240. Niessen CM. 2007. Tight junctions/adherens junctions: basic structure and function. J Invest Dermatol 127: 2525-2532. Nighot PK, Moeser AJ, Ryan KA, Ghashghaei T, Blikslager AT. 2009. ClC-2 is required for rapid restoration of epithelial tight junctions in ischemic-injured murine jejunum. Exp Cell Res 315: 110-118. Nishii N, Oshima T, Li M, Eda H, Nakamura K, Tamura A, Ogawa T, Yamasaki T, Kondo T, Kono T et al. 2020. Lubiprostone Induces Claudin-1 and Protects Intestinal Barrier Function. Pharmacology 105: 102-108. Ota T, Doi M, Yamazaki F, Yarimizu D, Okada K, Murai I, Hayashi H, Kunisue S, Nakagawa Y, Okamura H. 2014. Angiotensin II triggers expression of the adrenal gland zona glomerulosa-specific 3beta-hydroxysteroid dehydrogenase isoenzyme through de novo protein synthesis of the orphan nuclear receptors NGFIB and NURR1. Mol Cell Biol 34: 3880-3894. Perez-Rivas LG, Williams TA, Reincke M. 2019. Inherited Forms of Primary Hyperaldosteronism: New Genes, New Phenotypes and Proposition of A New Classification. Exp Clin Endocrinol Diabetes 127: 93-99. Rainey WE, Bird IM, Mason JI. 1994. The NCI-H295 cell line: a pluripotent model for human adrenocortical studies. Molecular and Cellular Endocrinology 100: 45-50. Rajamohan SB, Raghuraman G, Prabhakar NR, Kumar GK. 2012. NADPH oxidase-derived H(2)O(2) contributes to angiotensin II-induced aldosterone synthesis in human and rat adrenal cortical cells. Antioxid Redox Signal 17: 445-459. Rosol TJ, Yarrington JT, Latendresse J, Capen CC. 2001. Adrenal gland: structure, function, and mechanisms of toxicity. Toxicol Pathol 29: 41-48. Schewe J, Seidel E, Forslund S, Marko L, Peters J, Muller DN, Fahlke C, Stolting G, Scholl U. 2019. Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation. Nat Commun 10: 5155. Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A et al. 2012. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A 109: 2533-2538. Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V et al. 2018. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet 50: 349-354. Seidel E, Schewe J, Scholl UI. 2019. Genetic causes of primary aldosteronism. Exp Mol Med 51: 1-12. Slifer ZM, Blikslager AT. 2020. The Integral Role of Tight Junction Proteins in the Repair of Injured Intestinal Epithelium. Int J Mol Sci 21. Storbeck KH, Schiffer L, Baranowski ES, Chortis V, Prete A, Barnard L, Gilligan LC, Taylor AE, Idkowiak J, Arlt W et al. 2019. Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism. Endocr Rev 40: 1605-1625. Szekeres M, Turu G, Orient A, Szalai B, Supeki K, Cserzo M, Varnai P, Hunyady L. 2009. Mechanisms of angiotensin II-mediated regulation of aldosterone synthase expression in H295R human adrenocortical and rat adrenal glomerulosa cells. Mol Cell Endocrinol 302: 244-253. Tauber P, Aichinger B, Christ C, Stindl J, Rhayem Y, Beuschlein F, Warth R, Bandulik S. 2016. Cellular Pathophysiology of an Adrenal Adenoma-Associated Mutant of the Plasma Membrane Ca(2+)-ATPase ATP2B3. Endocrinology 157: 2489-2499. Thompson CH, Freeman CS, French RJ, McCarty Nael A. 2009. Pharmacological Characterization of GaTx2, a Peptide Inhibitor of ClC-2 Chloride Channels. Biophysical Journal 96. Tsukita S, Furuse M, Itoh M. 2001. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2: 285-293. Zennaro MC, Boulkroun S, Fernandes-Rosa F. 2015. An update on novel mechanisms of primary aldosteronism. J Endocrinol 224: R63-77. Zennaro MC, Jeunemaitre X, Boulkroun S. 2012. Integrating genetics and genomics in primary aldosteronism. Hypertension 60: 580-588. Zeydan B, Uygunoglu U, Altintas A, Saip S, Siva A, Abbink TEM, van der Knaap MS, Yalcinkaya C. 2017. Identification of 3 Novel Patients with CLCN2-Related Leukoencephalopathy due to CLCN2 Mutations. Eur Neurol 78: 125-127. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78271 | - |
| dc.description.abstract | 氯離子通道蛋白2 (Chloride channel protein 2，ClC-2) 是由人類CLCN2基因所編碼的蛋白。ClC-2廣泛表現於哺乳類組織的細胞膜上，對於調控細胞離子的平衡、細胞與細胞之間物質的運輸具有重要的角色。近年來發現CLCN2基因功能獲得型突變與第二型家族性高醛固酮症有關。醛固酮是由腎上腺皮質絲球帶所分泌，主要調控電解質的平衡。本篇研究即利用人類腎上腺皮質癌細胞株H295R，探討ClC-2對於醛固酮生成相關基因之影響，包括CYP11B2 (醛固酮合成酶) 及其他上游基因StAR、CYP11A1、HSD3B2及CYP21A2。另外，在ClC-2基因剔除小鼠中發現睪丸萎縮、塞特利氏細胞 (Sertoli cell) 異常及精子無法產生而導致雄性不孕。臨床上也發現CLCN2基因突變男性不孕症的案例。塞特利氏細胞之間有細胞連結會形成血液睪丸屏障，對於精子的生成是相當重要；因此我們也利用小鼠塞特利氏細胞株TM4，探討ClC-2對於屏障完整性之影響。 我們在H295R細胞使用三種處理，包括ClC-2 knockdown、ClC-2抑制劑GaTx2及ClC-2促進劑lubiprostone，觀察其對於醛固酮生成相關基因表現之效應。結果顯示，ClC-2 knockdown會降低CYP11B2、StAR及CYP11A1 mRNA的量；但是GaTx2處理，對這些基因的表現則都沒有影響。相反地，給予lubiprostone能促進CYP11B2、StAR及CYP21A2 mRNA的量，亦能提升StAR蛋白質的量，但不影響CYP11A1及HSD3B2的表現。上述結果說明ClC-2對醛固酮生成具有重要性。 在TM4細胞我們發現lubiprostone處理能顯著提升細胞跨膜電阻 (TER)，說明其可能增進細胞屏障的完整性；GaTx2處理對TER則沒有效應。分析TM4細胞連結蛋白質的表現量，ClC-2 knockdown、GaTx2及lubiprostone處理都沒有顯著效應。因此，lubiprostone在睪丸屏障的功能有待更多的研究。 | zh_TW |
| dc.description.abstract | Chloride channel protein 2 (ClC-2) is encoded by the human CLCN2 gene. ClC-2 is broadly expressed in the plasma membranes of epithelial cells from many mammalian tissues. ClC-2 plays an important role in regulating ion homeostasis and cell to cell communication. Recently, it has been found that patients with gain-of-function mutation of CLCN2 gene are associated with familial hyperaldosteronism type II. Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex, which regulates electrolyte homeostasis. In this study, we used human adrenocortical carcinoma cells H295R to investigate the effect of ClC-2 on expression of genes involved in aldosterone synthesis, including CYP11B2 (aldosterone synthase) and the upstream genes StAR, CYP11A1, HSD3B2 and CYP21A2. In addition, ClC-2 knockout mice suffered from testicular degeneration, abnormality of Sertoli cells and defective spermatogenesis that lead to male infertility. A case report demonstrated that a male with CLCN2 mutation had azoospermia. Blood-testis barrier is formed by Sertoli cells, which is important for spermatogenesis. We thus used mouse Sertoli cells TM4 to investigate the effect of ClC-2 on barrier integrity. We used three treatments in H295R cells, including ClC-2 knockdown, ClC-2 inhibitor GaTx2 and ClC-2 activator lubiprostone to test the effects on the expression of genes for aldosterone synthesis. The results revealed that knockdown of ClC-2 decreased the mRNA levels of CYP11B2, StAR and CYP11A1. However, these effects were not observed by GaTx2 treatment. Conversely, lubiprostone could promote the expression levels of CYP11B2, StAR and CYP21A2 mRNA and also StAR protein, but no effect on CYP11A1 and HSD3B2. These results indicated that ClC-2 plays a critical role in aldosterone synthesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:48:48Z (GMT). No. of bitstreams: 1 U0001-1108202012452900.pdf: 2683623 bytes, checksum: 2a3b5ea4e43fc9ca7aa86ea95aecd5cf (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 誌謝 I 目錄 II 表次 III 圖次 IV 摘要 VI Abstract VII 第一章 序論 1 一、 氯離子通道蛋白2 (Chloride channel protein 2，ClC-2) 的簡介 1 二、 類固醇荷爾蒙生成 1 三、 皮質醇生成的調控機制 2 四、 醛固酮生成的調控機制 3 五、 醛固酮分泌異常 3 六、 原發性高醛固酮症 4 七、 睪丸 (testes) 功能與結構 5 八、 研究目的 6 第二章 材料與方法 7 一、 細胞培養 7 二、 藥品 7 三、 蛋白質萃取 8 四、 西方墨點法 (Western blot) 9 五、 RNA萃取 11 六、 即時性反轉錄聚合酶連鎖反應 (Real-time RT PCR) 12 七、 shRNA knockdown 14 八、 跨膜電阻的測定Transepithelial electrical resistance (TER) 16 九、 統計分析 16 第三章 結果 17 一、 Angiotensin II (Ang II) 與K+參與醛固酮生成的調控 17 二、 8-bromo-cAMP對於CYP11B2、StAR及CYP11A1蛋白表現之影響 17 三、 ClC-2在腎上腺與睪丸塞特利氏細胞的表現 18 四、 ClC-2在H295R細胞對於醛固酮生成相關基因表現量之影響 18 1. CYP11B2 18 2. StAR 19 3. CYP11A1 19 4. HSD3B2 19 5. CYP21A2 20 五、 ClC-2在TM4細胞對於屏障完整性之影響 20 1. ClC-2於TM4細胞對於transepithelial electrical resistance (TER) 之影響 20 2. ClC-2於TM4對於細胞連結表現量之影響 20 第四章 討論 22 一、 Ang II、K+以及8-bromo-cAMP對於醛固酮生成影響之調控 22 二、 ClC-2在H295R細胞對於醛固酮生成基因表現之影響 22 三、 ClC-2在TM4細胞對於屏障完整性之影響 24 參考文獻 26 | |
| dc.language.iso | zh-TW | |
| dc.subject | 塞特利氏細胞 | zh_TW |
| dc.subject | 血睪屏障 | zh_TW |
| dc.subject | 腎上腺皮質細胞 | zh_TW |
| dc.subject | 醛固酮生成 | zh_TW |
| dc.subject | ClC-2 | zh_TW |
| dc.subject | ClC-2 | en |
| dc.subject | Sertoli cells | en |
| dc.subject | adrenocortical cells | en |
| dc.subject | BTB | en |
| dc.subject | aldosterone synthesis | en |
| dc.title | ClC-2於人類腎上腺皮質細胞H295R對於醛固酮生成以及小鼠塞特利氏細胞TM4屏障完整性之影響 | zh_TW |
| dc.title | Effect of ClC-2 on aldosterone synthesis in human adrenocortical carcinoma cells H295R and barrier integrity in mouse Sertoli cells TM4 | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 湯志永(Chih-Yung Tang),鄭瓊娟(Chung-Jiuan Jeng),楊豐名(Feng-Ming Yang) | |
| dc.subject.keyword | ClC-2,醛固酮生成,腎上腺皮質細胞,塞特利氏細胞,血睪屏障, | zh_TW |
| dc.subject.keyword | ClC-2,aldosterone synthesis,adrenocortical cells,Sertoli cells,BTB, | en |
| dc.relation.page | 51 | |
| dc.identifier.doi | 10.6342/NTU202002921 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2020-08-13 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生理學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-11 | - |
| 顯示於系所單位： | 生理學科所 | |
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