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Pathophysiological roles of Anoctamin 1 in the development of benign prostatic hyperplasia : 전립선 비대증에서 Anoctamin1의 병태생리학적 기능 연구

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dc.contributor.advisor오우택-
dc.contributor.authorCha Joo Young-
dc.date.accessioned2017-07-14T01:51:26Z-
dc.date.available2017-07-14T01:51:26Z-
dc.date.issued2015-08-
dc.identifier.other000000066803-
dc.identifier.urihttps://hdl.handle.net/10371/122407-
dc.description학위논문 (박사)-- 서울대학교 융합과학기술대학원 : 분자의학 및 바이오제약학과, 2015. 8. 오우택.-
dc.description.abstractBenign prostate hyperplasia (BPH) is characterized by enlargement of the prostate, causing lower urinary tract symptoms in elderly men worldwide. However, the molecular mechanism underlying the pathogenesis of BPH is unclear. Anoctamin1 (ANO1) encodes a Ca2+-activated chloride channel (CaCC) that mediates various physiological functions. Here we demonstrate that it is essential for testosterone-induced BPH. ANO1 was highly amplified in dihydrotestosterone (DHT)-treated prostate epithelial cells, whereas the selective knockdown of ANO1 inhibited DHT-induced cell proliferation. Three androgen-response elements were found in the ANO1 promoter region, which were relevant for the DHT-dependent induction of ANO1. Administration of an ANO1 blocker or Ano1 small interfering RNA inhibited prostate enlargement and reduced histological abnormalities in vivo. We therefore concluded that ANO1 is essential for the development of prostate hyperplasia and is a potential target for the treatment of BPH.-
dc.description.tableofcontentsAbstract i
Table of Contents iii
List of Figures viii
List of Table x
Introduction 1
1. Chloride Channel 1
1.1 Overview 1
1.2 Classification of Chloride Channel 2
1.2.1 ClC Channels 2
1.2.2 Cystic Fibrosis Conductance Regulator 3
1.2.3 GABA/glycine Receptors 4
1.2.4 Calcium-activated Chloride Channel 5
1.3 Calcium-activated Chloride Channel 5
1.3.1 Physiological Role of CaCCs 6
1.3.1.1 Fluid Secretion 6
1.3.1.2 Smooth Muscle Contraction 7
1.3.1.3 Regulation of Cardiac Excitability 7
1.3.1.4 Kidney 8
1.3.1.5 Endothelial Cells 8
1.3.2 Mechanism of Activation 9
2. TMEM 16 Family 9
2.1 Overview 9
2.2 Topology of the TMEM16 Proteins 11
2.3 Pathophysiological Functions of Anoctamin Paralogues 12
2.3.1 ANO1 12
2.3.2 ANO2 14
2.3.3 ANO6 15
2.3.4 ANO7 16
2.3.5 ANO10 16
2.4 Role of ANO1 in cell proliferation 17
3. Benign Prostatic Hyperplasia 18
3.1 Signs and Symptoms 18
3.2 Etiology 18
3.3 Pathophysiology 19
3.4 Diagnosis 19
3.5 Epidemiology 20
3.6 Therapeutics 20
Purpose of This Study 22
Methods 24
1. Cell Culture and Transfection 24
2. Human specimens 25
3. Western Blot 25
4. Patch Clamp Recording 26
5. Immunofluorescence 27
6. Reporter Gene Assay 28
7. Chromatin Immunoprecipitation assay 29
8. Rat BPH model 30
9. in vivo siRNA Rat BPH model 31
10. Immunohistochemistry and Histopathology 31
11. Statistics 32
Results 33
1. DHT increases ANO1 expression in human prostate epithelial cells 33
2. Activation of the ANO1 promoter-driven luciferase reporter gene in RWPE-1 cells 37
3. A Chromatin Immunoprecipitation (ChIP) assay for the AR binding to the ANO1 promoter in RWPE-1 cells 43
4. Ano1 knockdown abolishes DHT-induced prostate cancer cell proliferation 46
5. CACC blockers inhibit DHT-induced prostate cancer cell proliferation 50
6. DHT induces ANO1 currents in RWPE-1 cells 54
7. CACC blockers inhibit Ca2+-activated ANO1 currents in RWPE-1 cells 59
8. Tannic acid suppresses prostate enlargement in rat BPH model 61
9. ANO1 expression increased in prostate tissues from rat BPH model 65
10. In-vivo knockdown of Ano1 reduces prostate hyperplasia in rat BPH model 70
11. Intraprostatic injection of Ano1 siRNA suppresses cell proliferation in rat BPH model 82
12. ANO1 expression is increased in BPH patient samples 89
Discussion 93
References 98
국문초록 113		-
dc.formatapplication/pdf-
dc.format.extent4089540 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 융합과학기술대학원-
dc.subjectAnoctamin 1 (ANO1)-
dc.subjectBenign Prostate Hyperplasia (BPH)-
dc.subjectProliferation-
dc.subject.ddc610-
dc.titlePathophysiological roles of Anoctamin 1 in the development of benign prostatic hyperplasia-
dc.title.alternative전립선 비대증에서 Anoctamin1의 병태생리학적 기능 연구-
dc.typeThesis-
dc.contributor.AlternativeAuthor차주영-
dc.description.degreeDoctor-
dc.citation.pages114-
dc.contributor.affiliation융합과학기술대학원 분자의학 및 바이오제약학과-
dc.date.awarded2015-08-
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