To elucidate the molecular cell biology of vascular complications of the kidney and eye in diabetes, with a view to improving clinical intervention and patient care.Introduction
Diabetes and obesity are closely linked conditions that have already reached pandemic levels worldwide. Apart from the direct risks from diabetes and obesity (closely linked to Metabolic syndrome), serious vascular complications are a leading cause of morbidity and mortality in diabetic patients. Chronic levels of high glucose during diabetes damage blood vessels in tissues that cause hypoxia/ischaemia and leads to serious diseases such as kidney failure and blindness.
Complexity of regulation of Bone Morphogenetic Protein signalling (Walsh et al., Trends Cell Biol, 2010). Secreted, glycosylated antagonists such as Grem1 bind to BMPs in the extracellular space and prevent their binding to cognate receptors.
Research to date
My laboratory is primarily focussed on signal transduction mechanisms that contribute to diabetic damage in the kidney and eye, with a view to developing new therapies to treat both of these diseases in patients.
For the last 6 years my laboratory has determined the role of several signalling molecules in diabetic kidney disease. Gremlin, a bone morphogenetic protein antagonist, is increased in diabetic kidney disease (Walsh et al., 2008), and we also showed that mice lacking one copy of the Gremlin gene are protected from diabetic kidney disease (Roxburgh et al., 2009). We have also identified that Jagged1/Notch, important developmental proteins, are also increased in diabetic kidney disease, and we recently showed that the Jagged1/Notch pathway is required for TGF?1-mediated kidney epithelial cell damage (Nyhan et al., 2010). A protein essential for insulin action in vivo, insulin receptor substrate-2 (IRS2), is also important for brain and eye development. Our laboratory recently showed that mice lacking IRS2 had smaller kidneys and defective Akt signalling (Carew et al., 2010).
We have recently started to focus on a form of vascular stem cell called outgrowth endothelial cells (OECs) as a potential treatment for hyperoxia-induced damage in the retina of premature infants. These cells are circulating progenitors that are recruited to the site of hypoxia/ischaemia in the heart, lower leg and eye to mediate repair of damaged blood vessels in diabetes.
Current Research Projects
Responses of outgrowth endothelial cells to hypoxia/ischaemia
Funded by DEL (Imran Ali, PhD Student)
We are charactering the response of these cells in the ischaemia environment using primary OEC cells obtained from umbilical cords and a hypoxia chamber to establish the responses of these cells in 1 % oxygen. Initial results highlight specific early and later responses in gene expression and signal transduction pathway activation. Of particular note are the BMP pathway and changes in PI3kinase/Akt/p70S6kinase signalling.
Strategy to utilize outgrowth endothelial cells for the treatment of ROP and diabetic complications. OECs can be isolated from adults or umbilical cord, grown in vitro and then transferred back into the patient in an autologous manner.
Towards a novel, cell-based therapy for retinopathy of prematurity (ROP)
Funded by Action Medical Research (Dr. Michelle Hookham, Postdoctoral Fellow)
Retinopathy of prematurity (ROP) is a serious complication of early birth in infants born earlier than 32 weeks. Changes in oxygen tension in the retina cause an ischaemic insult followed by a proliferative response of blood vessels which can lead to blindness. The current therapy of choice is laser photocoagulation, although recent data suggests that targeting VEGF may provide benefit in these patients. We are characterising the potential of outgrowth endothelial cells for the treatment of ROP. In collaboration with clinical colleagues Dr. Eibhlin McLoone and Dr. David Sweet, we will collect OECs from premature infant umbilical cords and assess their endothelial properties and angiogenic potential. These data will indicate if autologous transplant of OECs from premature infants has value for the treatment of ROP.
The role of Gremlin1, a bone morphogenetic antagonist, in diabetic microvascular complications
Funded by BBSRC CASE and Diabetes UK (Rachel Church, PhD Student and Dr. Arjun Krishnakumar, Postdoctoral Fellow)
Gremlin 1 (Grem1) is an antagonist of bone morphogenetic protein that is crucial for developmental processes such as kidney formation. Our group has shown that Grem1 levels are elevated in diabetic kidney disease (DN) and we have previously shown that mice lacking grem1 are protected from early DN-like changes in kidney. We are now focussed on determining the exact mechanism of Grem1-BMP interaction using mass spectrometry to allow us to monitor the progression DN and other diabetic complications. In addition, we will generate novel models to identify the precise role of Grem1 in the kidney during diabetes using a range of techniques.
Gremlin1 plays a key role in development and disease. Mutations in Grem1 and other antagonists such as Noggin cause defects in digit formation. In addition, Grem1 levels are upregulated in diabetic kidney
Dr. Michelle Hookham (Postdoctoral Fellow funded by Action Medical Research)
Imran Ali (PhD Student funded by DEL)
Rachel Church (PhD Student funded by BBSRC CASE/Astra Zeneca)
Dr. Sarah Chamney (Clinical Ophthalmology Fellow)
Olivia O'Leary (PhD Student - Co-Supervised with Prof. Alan Stitt from October 2011)
Queen's University Belfast
Prof. Chris Elliot Dr. Eibhlin McLoone
Dr. David Sweet Prof. Peter Maxwell
Dr. Brian Hemmings FRS (FMI Basel)
Prof. Morris White (Children's Hospital, Harvard Medical School, Boston)