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)