| Abstract | 第6-8页 |
| 中文摘要 | 第9-11页 |
| Abbreviations | 第11-13页 |
| List of Tables | 第13-14页 |
| List of Figures | 第14-16页 |
| Chapter 1 Introduction | 第16-46页 |
| 1.1 Germ cell development and reproductive disease | 第16-25页 |
| 1.1.1 Specification, migration and proliferation of germ cell during embryonic stage | 第16-19页 |
| 1.1.2 Postnatal oogenesis | 第19-22页 |
| 1.1.3 Postnatal spermatogensis | 第22-25页 |
| 1.2 RNA binding protein and study of Nanos | 第25-33页 |
| 1.2.1 RNA binding protein | 第25-28页 |
| 1.2.2 Evolutional conserved role of Nanos gene in germ cell development | 第28-30页 |
| 1.2.3 Role of Nanos family in mammalian | 第30-33页 |
| 1.3 Human reproductive defects and clinical research | 第33-37页 |
| 1.4 Circadian rhythms and its physiological functions | 第37-40页 |
| 1.5 Genetic modified mouse model and its application in human disease study | 第40-46页 |
| 1.5.1 Methods for genetic modification in mice | 第41-44页 |
| 1.5.2 Challenges in using mouse models for studying human disease | 第44-46页 |
| Chapter 2 A NANOS3 mutation linked to protein degradation causes premature ovarian insufficiency | 第46-72页 |
| 2.1 Introduction | 第46-47页 |
| 2.2 Material and methods | 第47-54页 |
| 2.3 Results | 第54-70页 |
| 2.3.1 Identification of SNPs in POI patients and biochemical analysis of a novel SNP in NANOS3 | 第54-58页 |
| 2.3.1.1 Identifying NANOS family mutations in POI patients | 第54页 |
| 2.3.1.2 Characterizing the Novel SNP in NANOS3 | 第54-55页 |
| 2.3.1.3 R153W mutation influence hNANOS3 stability but not cell location | 第55-57页 |
| 2.3.1.4 hNANOS3 R153W is degradated by proteasome pathway | 第57-58页 |
| 2.3.2 Failure of recapitulating the phenotype of human patients in mouse model | 第58-60页 |
| 2.3.2.1 Construction of mouse model | 第58-60页 |
| 2.3.2.2 Morphology analysis of mutant heterozygous and homozygous mice | 第60页 |
| 2.3.3 Analysis of potential causes of different phenotype in mouse and human | 第60-63页 |
| 2.3.3.1 mNANOS3 is more stable than human NANOS3 and effect of mutation on mouse NANOS3 is does dependent | 第60-61页 |
| 2.3.3.2 A single amino acid substitution led to significant protein stability changes | 第61-63页 |
| 2.3.4 Recapitulate phenotype of patient in modified mouse model | 第63-70页 |
| 2.3.4.1 Effect of R133W was pronounced under Nanos3 knockout background | 第63-67页 |
| 2.3.4.2 Confirmation of effect of R133W in Nanos3~(Neo/Neo) mouse model | 第67-70页 |
| 2.4 Discussion | 第70-72页 |
| Chapter 3 Identify targets of Nanos3 and its role in postnatal male germ cell survival | 第72-83页 |
| 3.1 Introduction | 第72-73页 |
| 3.2 Material and methods | 第73-74页 |
| 3.3 Results | 第74-81页 |
| 3.3.1 Nanos3 is essential for germ cell survival in postnatal male but not female gonad | 第74-78页 |
| 3.3.2 Identification of RNA target of NANOS3 | 第78-81页 |
| 3.4 Discussion | 第81-83页 |
| Chapter 4 The Circadian Clock Influences Heart Performance | 第83-104页 |
| 4.1 Introduction | 第83-85页 |
| 4.2 Material and methods | 第85-87页 |
| 4.3 Results | 第87-100页 |
| 4.3.1 Cardiac ejection fractions exhibit daily variations | 第87-89页 |
| 4.3.2 Disruption of the circadian clock impairs diurnal EF variation | 第89-92页 |
| 4.3.3 The circadian clock is disrupted in Pgc1 α transgenic mice | 第92-96页 |
| 4.3.4 Diurnal variations in EF and FS are blunted in Pgc1 α transgenic mice | 第96页 |
| 4.3.5 Circadian variations in EF and FS are modulated by PGC1α/PPARα | 第96-100页 |
| 4.4 Discussion | 第100-104页 |
| Reference | 第104-116页 |
| Acknowledgements | 第116-117页 |
| Publications | 第117-119页 |
