Carbonyl Reductase 1 and 20β-Dihydrocortisol: a novel glucocorticoid metabolism pathway in the pathogenesis of mineralcorticoid activation in obesity. (360G-Wellcome-206587_Z_17_Z)
Dysregulation of the balance of corticosteroid action via glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) contributes to inflammation, cardiovascular and metabolic disease. I have discovered a novel pathway of cortisol metabolism by the cytosolic enzyme carbonyl reductase 1 (CBR1) producing 20beta-dihydrocortisol (20beta-DHF), a weak agonist of glucocorticoid receptor (GR) but a potent mineralocorticoid receptor (MR) agonist. I have shown that CBR1/20beta-DHF is up-regulated in obesity, specifically in adipose, in humans and animals. In obese mice, CBR1 inhibition enhanced hepatic GR signalling (associated with greater glucose intolerance) but reduced renal MR signalling. I hypothesise that up-regulation of CBR1 in obesity leads to increased MR activation, contributing to hypertension and adipose dysfunction. To test this hypothesis I will generate an in vitro model with independent GR- and MR-responsive reporters and test the effects of CBR1. I will determine MR binding and downstream effects of 20beta-DHF in vivo; test the effects of global Cbr1 knockout and adipose-specific Cbr1 overexpression on MR activation in murine obesity.
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Grant Details
Amount Awarded | 477201 |
Applicant Surname | Morgan |
Approval Committee | Clinical Interview Committee |
Award Date | 2017-05-25T00:00:00+00:00 |
Financial Year | 2016/17 |
Grant Programme: Title | Clinical Research Career Development Fellowship |
Internal ID | 206587/Z/17/Z |
Lead Applicant | Dr Ruth Morgan |
Partnership Value | 477201 |
Planned Dates: End Date | 2022-03-01T00:00:00+00:00 |
Planned Dates: Start Date | 2017-09-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Scotland |
Sponsor(s) | Prof Brian Walker |