Diabetic Complications Laboratory
Role of CDA1 in TGF-b Signaling in Diabetic Complications
The complication conditions of diabetic patients include macrovascular disease, which directly causes myocardial infarction, stroke and peripheral vascular disease, and microvascular conditions including kidney failure and blindness. These complications are the leading causes of the increased morbidity and mortality in the patients of diabetes.
In the sites of diabetic injury including blood vessels and kidney, a number of key cellular response events occur for the purpose of repairing the damaged tissues. These include the cell differentiation and proliferation at the early stage, followed by excess accumulation of extracellular matrix proteins, a condition called fibrosis or tissue scarring, at the later stage if the damage is too severe to be repaired. The tissue scarring represents a failed repair of damaged tissues or loss of functional tissues/cells, which is seen in heart failure, kidney failure and atherosclerosis.
Cell Division Autoantigen 1 (CDA1) is a molecule recently identified and cloned by our group. It is well established that CDA1 modulates TGF-b receptor kinases and activates multiple important intracellular signaling pathways including Smad, MEK/ERK MAPK and p53, ultimately leading to impaired tissue repair and scarring. Elevated CDA1 expression levels are found in diabetes-induced atherosclerosis and advanced diabetic nephropathy, where severe tissue scarring or fibrosis is present. The role of the elevated levels of CDA1 in the development of these diseases is directly shown by the ability of CDA1 to stimulate gene expression of collagen and other extreacellular matrix proteins in cultured cells. Targeting CDA1 by siRNA in cells prevent TGF-b stimulated gene expression of collagen I and III, showing that CDA1 is an attractive molecular target for drug development in order to prevent and treat chronic diabetic complications associated with tissue scarring.
Our research is currently funded by Jurvenile Diabetes Research Foundation, Australian National Health & Medical Research Council and National Heart Foundation of Australia. We are also founded by a commercial partner company, Dia-B Tech P/L.
The research projects available for Honors and/or PhD include:
- molecular mechanisms of CDA1 in regulating DNA damage response
- role and mechanism of CDA1 in regulating extracellular matrix protein production in vascular and kidney cells
- development of approaches to target CDA1 for application in diabetic complications. The techniques used in the lab include most of the molecular biology and cell biology techniques, including:
- cell culture and recombinant DNA technology
- retrovirus and adenovirus directed gene expression
- RNA interference technology
- yeast 2-hybrid system for protein-protein interaction study
- Western blot and real-time RT-PCR.
