Vascular Cell Biology
This section focuses on the basic pathogenesis of diabetes-induced microvascular and cardiovascular pathologies, relevant to both type 1 and type 2 diabetes These complications are the major causes of blindness, kidney failure and amputation in adult Americans.
The investigators study how glucose alters signaling and function in cultured vascular cells, and have analyzed actions of hormones and cytokines such as insulin, VEGF, endothelin, CTGF and angiotensin on vascular cells. Translational research efforts determine whether the results from cultured cells and animal models can be extrapolated to patients with type 1 and type 2 diabetes.
The section has established cultured vascular cells from retina, renal glomeruli, myocardium, and large arteries from rodents and humans. Using these cells, it has employed cutting-edge methods of cell biology, imaging, genomics & proteomics, molecular biology, animal physiology and drug design to understand the pathobiology of, and to design therapeutics for, diabetic vascular complication including diabetic retinopathy, macular edema, nephropathy, cardiovascular diseases and cerebral vascular strokes.
Clinical studies based on Joslin Medalist patients who have had type 1 diabetes for 50 years have begun to identified potential protective factors against the development of vascular complications using a combination of clinical, biochemical and proteomic analysis of the retina and renal tissues donated by the Medalists.
From all the studies, our section has identified VEGF as the cause and now anti-VEGF as a proven treatment of proliferative diabetic retinopathy, pioneered the idea that PKC activation being an important mechanism of vascular complications, kallikrain pathway activation as causing macular edema and strokes and reporting SHP-1, a tyrosine phosphatase, causing the deactivation of PDGF's protective actions in the retina.
Recent publication “highpoints”:
- Demonstration of persistence and function of insulin-producing pancreatic β cells in patients with type 1 diabetes for >50 years suggests the possibility of a steady state of turnover of endogenous β cells, suggesting opportunities to increase β cell mass even after long duration. Diabetes 2010
- Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab. 2010
- Hyperglycemia exacerbates retinal hemorrhage and strokes, an effect that is reduced by plasma kallikrein deficiency or inhibition. Nat. Med. 2007, 2011
- The PKC-β-selective inhibitor, ruboxistaurin, which was discovered at Joslin, is clinically effective in preserving vision. Orally administered ruboxistaurin reduced visual loss in patients with moderate to severe non-proliferative diabetic retinopathy. FASEB J 2006, Retina 2011
- Demonstrating that hyperglycemia can cause pre-mature apoptosis of retinal pericytes by two pathways of toxic metabolites and activation of SHP-1, a tyrosine phosphatase, to deactivate protective factors such as PDGF with tyrosine kinase receptors in the retina. Nature Medicine, Nov., 2009