| Abstract | 第6-8页 |
| 中文摘要 | 第9-12页 |
| Abbreviations | 第12-14页 |
| Chapter Ⅰ:Introduction | 第14-48页 |
| Introduction | 第15-16页 |
| 1. The ovary | 第16-21页 |
| 1.1 The ovary structure | 第16页 |
| 1.2 Ovarian reserve | 第16-17页 |
| 1.3 Folliculogenesis | 第17-20页 |
| 1.4 Follicular atresia | 第20-21页 |
| 2. Premature ovarian failure (POF) | 第21-25页 |
| 2.1 Diagnosis of POF | 第21-22页 |
| 2.2 Etiologic mechanisms of POF | 第22-24页 |
| 2.3 Genetically modified mouse models for POF | 第24-25页 |
| 3. p53 family | 第25-31页 |
| 3.1 p53 | 第25-30页 |
| 3.1.1 p53:guarding the genome | 第25-26页 |
| 3.1.2 Structure of p53 | 第26-27页 |
| 3.1.3 Regulation of p53 activity by MDM2 | 第27-29页 |
| 3.1.4 Deleterious effects of uninhibited p53 in normal tissues | 第29-30页 |
| 3.2 p63/p73 | 第30-31页 |
| 4. p53 family and female reproduction | 第31-35页 |
| Summary and prospective | 第35-36页 |
| References | 第36-48页 |
| Chapter Ⅱ:Role of MDM2-p53 pathway in follicular survival anddevelopment | 第48-110页 |
| Introduction | 第50-53页 |
| Materials and methods | 第53-61页 |
| Results | 第61-105页 |
| Section 2.1 Mdm2 deletion in mouse oocytes at the primordial follicle stage resulted infemale infertility and accelerated ovarian aging | 第61-70页 |
| 2.1.1 Generation of mice with oocyte-specific Mdm2 deletion at the primordial follicle stage | 第61-62页 |
| 2.1.2 Mdm2 deletion in oocytes at the primordial follicle stage resulted in female infertility and accelerated ovarian follicle loss | 第62-65页 |
| 2.1.3 Mdm2 deletion in oocytes has no significant impact on meiotic progression | 第65-66页 |
| 2.1.4 Reduced survival of primordial follicles in Mdm2Gdf9 cKO mice | 第66-69页 |
| 2.1.5 Conclusion | 第69-70页 |
| Section 2.2 Mdm2 deletion in oocytes of the primary follicle stage led to oocytedegeneration and a block in folliculogenesis | 第70-78页 |
| 2.2.1 Deletion of Mdm2 using Zp3-Cre | 第70-71页 |
| 2.2.2 Deletion of Mdm2 using Zp3-Cre led to decreased fertility and POF in Mdm2Zp3 cK O mice | 第71-73页 |
| 2.2.3 Deletion of Mdm2 in oocytes of the primary follicle stage led to a block in folliculogenesis | 第73-77页 |
| 2.2.4 Conclusion | 第77-78页 |
| Section 2.3 Suppression of p53 in oocytes is critical for follicular growth anddevelopment | 第78-87页 |
| 2.3.1 Concurrent deletion of p53 in oocytes reversed the excessive follicular loss caused by the deletion of Mdm2 | 第78-82页 |
| 2.3.2 p53 dependent oocyte death induced by Nutlin-3 | 第82-86页 |
| 2.3.3 Conclusion | 第86-87页 |
| Section 2.4 p53 is tightly regulated by MDM2 in oocytes duringfolliculogenesis | 第87-92页 |
| 2.4.1 Expression of Mdm2 during folliculoegenesis and early embryogenesis | 第87-88页 |
| 2.4.2 Increased nuclear intensity of p53 in oocytes of Mdm2Gdf9 cK O and Mdm2Zp3 cKO mice | 第88-91页 |
| 2.4.3 Increased nuclear intensity of p53 in oocytes of Nutlin-3 treated ovaries | 第91-92页 |
| 2.4.4 Conclusion | 第92页 |
| Section 2.5 MDM2 inhibited p53 activation in the presence of drugs that inducedribosomal stress in oocytes | 第92-100页 |
| 2.5.1 Ribosomal stress induced p53 accumulation in granulosa cells | 第92-96页 |
| 2.5.2 5-FU increased p53 protein in oocytes of Mdm2-Mdm4Gdf9 cKOmice | 第96-99页 |
| 2.5.3 Conclusion | 第99-100页 |
| Section 2.6 p53 deletion protected the mice from DXR induced follicularloss | 第100-105页 |
| 2.6.1 DXR induced increased p53 expression in granulosa cells of the ovary | 第100-102页 |
| 2.6.2 p53 deletion protected the ovary from DXR induced damage | 第102-104页 |
| 2.6.3 Conclusion | 第104-105页 |
| Summary and Discussion | 第105-110页 |
| Appendix 1 | 第110-111页 |
| Appendix 2 | 第111-112页 |
| References | 第112-118页 |
| 致谢 | 第118-119页 |
| Publications | 第119-121页 |
