Title Page
Abstract
Contents
Introduction 10
Material and Methods 15
Results 34
Discussion 85
Reference 89
국문초록 99
Fig. 1. Schematic representation of senescence regulatory pathways 52
Fig. 2. Schematic model of ABCA1 homeostasis. 53
Fig. 3. Cholesterol metabolism is altered in senescent cells. 55
Fig. 4. Cholesterol metabolism is altered during replicative senescence and oncogene-induced senescence. 57
Fig. 5. Altered Cholesterol metabolism modulates senescence-associated inflammation. 58
Fig. 6. Orthogonal cholesterol modulation affects senescence-associated inflammation. 59
Fig. 7. Cholesterol metabolism is involved in SASP regulation during OIS. 60
Fig. 8. ABCA1 is necessary for inducing SASP in senescent cells. 61
Fig. 9. ABCA1 deletion abrogated SASP induction during different senescent models. 63
Fig. 10. Different genes in cholesterol metabolism are irrelevant to SASP activation. 64
Fig. 11. The GATA4-NF-kB axis induces ABCA1 during senescence. 65
Fig. 12. ABCA1 regulates the SASP through the mTORC1 pathway. 67
Fig. 13. ABCA1 is localized in lysosome and functions as a lysosomal cholesterol importer. 69
Fig. 14. Probucol enhanced lysosomal pools of ABCA1 resulting in lysosomal cholesterol accumulation and mTOR-SASP activation. 71
Fig. 15. Pharmacological modulation of lysosomal cholesterol affects the SASP. 72
Fig. 16. Lysosomal cholesterol accumulated by ABCA1 contributes to microdomains enriched for the mTORC1 scaffolding complex. 74
Fig. 17. ABCA1 sustains a lysosomal mTORC1 recruitment during senescence. 76
Fig. 18. Lysosomal amino acid levels do not change during senescence. 77
Fig. 19. Control of lysosomal cholesterol modulates primary mouse chondrocytes senescence. 78
Fig. 20. Control of lysosomal cholesterol modulates in vivo senescence during OA progression. 80
Fig. 21. Cholesterol metabolism and ABCA1 modulate nociception related behavioral defects during OA progression. 82
Fig. 22. Expression of ABCA1 is associated with the SASP signature and inflammation in multiple tissues during human ageing... 83