Dr. Nayek made the interesting observation that anti-pericyte antibodies can be detected in the blood of appreciable numbers of Type I diabetic patients. This antibody can be detected in one-third to one-half of all type 1 diabetics as opposed to only 6 percent of non-diabetic controls. The present proposal offers three specific aims to further characterize this antibody and its physiologic effects in retina. The first specific aim will be to identify pericyte antigens that are recognized by the circulating autoantibodies. These studies will be conducted using cultured bovine pericytes, and focus on the endothelin and/or fibronectin receptors. The target of the antibodies will be immunoprecipitated and sequenced. In parallel studies, pericyte endothelin and fibronectin receptors will be purified and affinity of the antibody binding to them studied. Cells in which the ETa and b receptors are expressed will be used also to identify targets of the antibody.
In specific aim 2, effects of the antibody on pericyte structure and signal transduction pathways will be studied in vitro, and on retinal physiology in vivo by measuring effects on retinal blood flow and on the autoregulatory response of blood flow to 100% oxygen. Effects of the antibody on release of arachidonic acid, formation of inositol phosphate, and distribution and orientation of cellular actin and myosin will be assessed ti begin understanding the effect of the antibody on retinal blood flow.
Specific aim 3 will establish whether or not the anti-pericyte antibody in diabetic patients are associated with IgG allotype (G2m(23)+) that has been reported to be associated with diabetic retinopathy. The presence of the (Gm(23)+) allotype will be stratified by the presence or absence of anti-pericyte autoantibody. Identification of pericyte membrane proteins recognized by both the anti-pericyte antibody and antibodies against (G2m(23)+) will be used to establish the likelihood that the two antibodies are the same.
|Nayak, Ramesh C; Lynch, Kristian; Gustavsson, Carin et al. (2007) Circulating antipericyte autoantibodies: a novel modifier of risk of progression of diabetic retinopathy? Retina 27:211-5|
|Nayak, Ramesh C; Agardh, Elizabet; Kwok, Michael G K et al. (2005) Albuminuria and hypertension are independently associated with circulating antipericyte autoantibodies in type 2 diabetic patients. Metabolism 54:188-93|
|Nayak, R C; Agardh, C D; Kwok, M G K et al. (2003) Circulating anti-pericyte autoantibodies are present in Type 2 diabetic patients and are associated with non-proliferative retinopathy. Diabetologia 46:511-3|
|Attawia, M A; Nayak, R C (1999) Circulating antipericyte autoantibodies in diabetic retinopathy. Retina 19:390-400|