Non-Enzymatic Glycation of Collagen: Role in Metabolic Disease and Inflammation

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Diabetes can lead to high levels of sugar in the blood and that sugar reacts with the proteins in our tissues, causing significant disruption of the tissues and impairment of their function. For this reason, diabetics suffer a range of problems like poor kidney function, so-called hardening of the arteries and are also at high risk of osteoporosis and severe osteoarthritis. The sugar that is considered primarily responsible for that process is glucose, as this is the sugar that has high, uncontrolled blood levels in diabetics. However, we have discovered that a sugar polymer called poly(ADP ribose), that is produced by cells under stress, is released into the surrounding tissue if the cell dies - which it may if it continues to be stressed - and that this polymeric sugar is very reactive with tissue proteins like collagen. The type of situation where a cell might be stressed is where there is chronic inflammation, for instance, or following a cut-off of oxygen. The high blood glucose levels in diabetics means that their tissues suffer significantly from chronic inflammation; however, there are many diseases and conditions in non-diabetics which result in chronic inflammation as well, of either specific tissues or the body's tissues in general. We know that chronic inflammation often results in impairment of the tissue's function and/ or stiffening of the tissue, for instance, chronic inflammation in joints results in osteoarthritis through degradation of the joint cartilage; chronic inflammation in arteries leads to the so-called "hardening of the arteries" - and we know that although these conditions are common in diabetics, they are also common in non-diabetics. This project will explore whether chronic inflammation in bones and blood vessels - for whatever reason - leads to poly(ADP ribose) in those tissues, which then reacts with the tissue proteins and causes the sort of tissue deterioration we see in those tissues after chronic inflammation. We think the high blood glucose levels causing chronic tissue inflammation throughout the body in diabetics, may lead to poly(ADP ribose) in the affected tissues and that it the poly(ADP ribose), which causes the damage to the tissue, rather than glucose directly. We think the primary role of the high glucose levels in diabetics is to cause the chronic inflammation conditions which lead to poly(ADP ribose) being released into the tissue. In this project, we will determine under what conditions cells might die and leave poly(ADP ribose) in the tissue around them and how this reacts with the tissue proteins, particularly collagen. We will then find out how the reaction of poly(ADP ribose) with the tissue proteins affects both the mechanical flexibility of the tissue and how the remaining live cells in the tissue behave once the proteins around them have reacted with poly(ADP ribose). We think that damage to collagen, the main protein in our tissues, caused by poly(ADP ribose) may be responsible for the onset of osteoporosis, at least in some cases, so we will also investigate how different the calcification of bone is after bone tissue has been disrupted by reaction with poly(ADP ribose). If we can identify what is causing the damage to tissues in chronic inflammation, then we can begin to devise strategies to control or perhaps even reverse that damage. This project will specifically look at bone and blood vessels as there are many diseases and conditions for which chronic inflammation is a feature, but if indeed poly(ADP ribose) is responsible for significant damage, then we will look at other conditions where chronic inflammation and cell necrosis are factors, such as neurodegenerative diseases like Alzheimers disease.