Measuring changes in circulating Gremlin levels as a diagnostic

MRes in Translational Medicine (2014-2015)
Research Project Summary
Project Title
Measuring changes in circulating Gremlin levels as a diagnostic marker of
diabetic kidney injury
Supervisor(s)
Dr. Derek Brazil/Prof. Tim Lyons/Dr. Jeremy Yu
Research Centre
Centre for Experimental Medicine
Principal
Supervisor’s
Contact Details
Background
information:
Email: d.brazil@qub.ac.uk
Aims / objectives
1. To measure levels of Gremlin using ELISA in plasma and urine from pregnant control
and preeclampsia patients in a prospective cohort of pregnant women with type 1
diabetes. We will use existing samples collected prospectively at all trimesters of
gestation.
Tel: 9063-2572
Gremlin is a secreted antagonist of the bone morphogenetic protein (BMP) family that
regulates multiple processes in development and disease. Gremlin levels are increased
in renal biopsies of patients suffering from diabetic kidney disease, and strategies that
target Gremlin attenuate the severity of fibrosis in diabetes and other kidney diseases.
Apart from its role as a BMP antagonist, recent data have identified Gremlin as a proangiogenic factor that signals via the VEGFR2 in endothelial cells.
Preeclampsia is a serious complication of pregnancy, especially in women with diabetes.
Preeclampsia is characterised by high blood pressure and proteinuria, attributed to
endothelial dysfunction caused by placental factors released into the maternal
circulation. Recent evidence suggests that altered angiogenic/anti-angiogenic balance is
involved in the development of maternal symptoms. Such alterations include increased
levels of soluble Flt1 and soluble Endoglin (sEng1) in plasma, antagonizing the normal
function of VEGF, TGF-β1 and PlGF. As a factor that modulates angiogenesis, we
hypothesize that Gremlin is likely to play a role in preeclampsia.
2. To correlate changes of Gremlin in plasma and/or urine with clinical characteristics,
blood pressure, HbA1c,degree of proteinuria, lipid profiles, and other established
preeclampsia markers such as sFlt1, sEng1, and PlGF
3. To measure levels of serum and urinary Gremlin in mouse models of diabetic
nephropathy and/or unilateral ureteral obstruction (UUO)
4. To examine Gremlin signalling in a placental trophoblast cell line using VEGFR2
receptor activation and BMP-9 inhibition as readouts
Successful completion of this project by the MRes student will define whether changes in Gremlin
are associated with increased risk of preeclampsia in human patients, as well as Gremlin levels in
mouse models of diabetic nephropathy and acute obstructive fibrosis.
Techniques
employed:
ELISA
Real time PCR
Histology
Western blotting
Statistical correlation analysis
Cell Culture