REGULATION OF TISSUE REMODELING IN AGING AND DIABETES

Project Details

Description

Glucose can react non-enzymatically with proteins to form time- stable covalent adducts called Advanced Glycosylation Endproducts (AGE), which are fluorescent, yellow-brown pigments with an ability to cross-link proteins and nucleic acids. The accumulation of AGE's on long-lived proteins in vivo has been found to increase linearly with age and is greatly accelerated in patients with diabetes. Recently, we have identified a specific receptor on monocytes/macrophages which is responsible for the uptake of AGE- modified proteins or cells. This AGE-protein removal formation reflects a time-dependent equilibrium reaction that is determined by the amount of glucose present. Binding of AGE-proteins to macrophages has also been found to lead to the synthesis and release of two important monokines, cachectin/TNF and IL-1. The release of these growth-promoting factors may represent a mechanism by which the macrophage signals to surrounding cells in the tissue microenvironment the removal of senescent proteins and the need for their replacement. In addition, the number and affinity of the AGE-receptor have recently been found to be modulated by insulin and cachectin/TNF in opposite directions; hypoinsulinemia down- regulates, while hypoinsulinemia and cachectin/TNF up-regulate this receptor system. The objectives of the current proposal are to determine: 1) the ability of AGE-proteins to induce macrophages from old and diabetic animals to release other growth factors and monokines known to participate in tissue remodeling, including Platelet-Derived Growth Factor (PDGF), Transforming Growth Factors-alpha and beta (TGF- alpha and TGF-beta), and Macrophage Inflammatory Proteins- 1 and 2 (MIP-1 and MIP-2); 2) the ability of cachectin/TNF and other monokines to enhance macrophage AGE-receptor expression; 3) the ability of cachectin/RNF to up-regulate the AGE-receptor in macrophages from old and diabetic (hypo- and hyperinsulinemic) animals; 4) the ability of cachectin/TNF to up-regulate the AGE- receptor in vivo. These studies should provide insight into important molecular events involved in normal tissue remodeling, as well as possible efficiency of the AGE-protein clearance system by carefully administering potent mediators such as cachectin/TNF to animals in low doses is of importance for evaluating our hypothesis on the role of AGE-proteins in ageing, as well as providing the rationale for possible therapeutic interventions.
StatusFinished
Effective start/end date1/07/8930/06/92

Funding

  • National Institute on Aging

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