Aging individuals succumb most frequently to vascular compromise, among various other complications. Diabetic patients suffer from a similar spectrum of problems, which, although mostly unrelated to insulin deficiency, have been clearly associated with hyperglycemia. The investigators have developed the central hypothesis that aging and diabetic complications are in part due to the covalent modification of tissue proteins by ambient glucose, forming time-stable adducts termed Advanced Glycosylation Endproducts (AGE). These irreversible reactive adducts increase linearly with age and at an accelerated rate in patients with diabetes. A macrophage receptor system specific for the removal of AGEs on senescent proteins and cells has been identified and characterized over the past 5 years. Ingestion and degradation of AGE-proteins by macrophages is followed by the synthesis of a host of cytokines and growth factors, suggesting a mechanism by which macrophages participate in tissue repair via this system. The AGE-receptor system appears to consist of two AGE-binding proteins, a 60 kD and a 90 kD, which have been purified and partially sequenced. Cellular aging and insulin excess have been identified as two important factors associated with a compromise in the efficiency of the macrophage receptors, possibly contributing to the acceleration of vascular dysfunction and hypertension associated with both aging and hyperinsulinemia. The objectives of the current proposal are: 1. To clone and sequence the genes of both AGE-receptor binding units, and to develop monoclonal antibodies, so as to proceed with the molecular and cell biology studies of the system, 2. To explore the regulation of expression and function of each AGE-binding protein at the mRNA and protein levels in response to various in vivo physiological and pathological states associated with Aging and Diabetes. 3. To study, the in vivo effects AGE accumulation in the vessels and kidney, two tissues which play a central role in the hypertension of diabetes and aging, using a novel AGE-animal model.
Showing the most recent 10 out of 22 publications
