| Research target |
Research question |
Predicted results |
| Sebocyte |
Regulatory role of FoxO1 in sebaceous lipogenesis;
FoxO1-mediated co-regulation of androgen receptor, PPARγ, LXR, RAR, RXR;
mechanism of isotretinoin-induced sebocyte apoptosis |
Decreased levels of nuclear FoxO1 in sebocytes in acne may stimulate sebaceous lipogenesis;
isotretinoin may induce sebocyte apoptosis by upregulation of nuclear FoxO1 and FoxO1-dependent apoptosis genes like IGFBP-3 and neutrophil gelatinase-associated lipocalin |
| Keratinocyte |
Investigation of the role of FoxO1 in keratincyte proliferation in the pilosebaceous unit (PSU) |
Decreased nuclear levels of FoxO1 in acro-infundibular keratinocytes in acne may be associated with decreased cyclin D1, D2 and increased p21 and p27 |
| Oxidative stress |
Clarification of the role of FoxO1 in oxidative stress responses of the PSU;
antioxidative mechanisms of isotretinoin action |
Downregulated nuclear FoxO1 in acne may result in increased oxidative stress with suppressed expression of FoxO1-regulated catalase and superoxide dismutase |
| Innate immunity |
Role of FoxO1 in the regulation of innate immunity of the PSU |
Downregulated nuclear FoxO1 in acne may decrease local innate immunity of the sebaceous follicle allowing P. acnes overgrowth and biofilm formation |
| Acquired immunity |
Influence of FoxO1 in T-cell regulation of the PSU;
Influence of isotretinoin on FoxO1-mediated T-cell regulation |
Reduced levels of nuclear FoxO1 in T-cells in PSU of acne patients; anti-inflammatory effect of isotretinoin or ectopeptidase inhibitors by upregulation of nuclear FoxO1 in T-cells |
| Dermal response |
Role of FoxO1 in matrix metalloproteinase (MMP) regulation and dermal remodeling |
Downregulated nuclear FoxO1 in acne may increase the activity of MMPs promoting increased dermal tissue destruction |
| Mode of retinoid action
Adverse drug effects of isotretinoin |
Clarification of the role of FoxO1 in isotretinoin´s mode of action;
Role of retinoids in FoxO-regulation; isotretinoin-induced hypertriglyceridemia, FoxO-1-mediated impairment of glucose metabolism, role of FoxOs in neurological adverse effects of isotretinoin |
Isotretinoin´s primary mode of action appears to be an increase of nuclear levels of FoxO1;
high levels of nuclear FoxO1 may be associated
with increased hepatic VLDL secretion, decreased apo-CIII-mediated VLDL hydrolysis by apo-CIII-dependent lipoprotein lipase, increased hepatic gluconeogenesis and increased neuronal levels of nuclear FoxO1with neurological alterations (mood disturbances) |
