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

糖尿病会导致血液中的糖含量过高，糖会与我们组织中的蛋白质发生反应，导致组织的严重破坏和功能的损害。因此，糖尿病患者会出现肾功能不佳、所谓的动脉硬化等一系列问题，而且患骨质疏松症和严重骨关节炎的风险也很高。葡萄糖被认为对这一过程负有主要责任，因为糖尿病患者血液中葡萄糖的含量很高，无法控制。然而，我们发现，细胞在压力下产生的一种叫做聚腺苷核糖（ADP核糖）的糖聚合物，如果细胞死亡，就会被释放到周围的组织中——如果细胞继续处于压力下，这种聚合糖可能会与胶原蛋白等组织蛋白发生反应。细胞可能受到压力的情况类型是慢性炎症，例如，或者在氧气切断之后。糖尿病患者的高血糖水平意味着他们的组织受到慢性炎症的严重影响；然而，在非糖尿病患者中，也有许多疾病和状况导致慢性炎症，无论是特定组织还是一般的身体组织。我们知道慢性炎症通常会导致组织功能的损害和/或组织的僵硬，例如，关节的慢性炎症通过关节软骨的降解导致骨关节炎；动脉的慢性炎症导致所谓的“动脉硬化”——我们知道，尽管这些情况在糖尿病患者中很常见，但在非糖尿病患者中也很常见。这个项目将探索骨骼和血管中的慢性炎症——无论出于什么原因——是否会导致这些组织中的聚（ADP核糖），然后与组织蛋白发生反应，导致慢性炎症后我们在这些组织中看到的那种组织恶化。我们认为，高血糖导致糖尿病患者全身慢性组织炎症，可能导致受影响组织中的聚（ADP核糖），而不是直接引起组织损伤的聚（ADP核糖）。我们认为糖尿病患者高血糖的主要作用是引起慢性炎症，导致多聚腺苷核糖被释放到组织中。在这个项目中，我们将确定在什么条件下细胞可能会死亡，并在周围的组织中留下聚（ADP核糖），以及它如何与组织蛋白，特别是胶原蛋白发生反应。然后，我们将了解聚（ADP核糖）与组织蛋白的反应如何影响组织的机械灵活性，以及一旦周围的蛋白质与聚（ADP核糖）发生反应，组织中剩余的活细胞如何表现。我们认为，至少在某些情况下，由聚（ADP核糖）引起的胶原蛋白（我们组织中的主要蛋白质）的损伤可能是骨质疏松症发病的原因，因此我们还将研究在骨组织被聚（ADP核糖）反应破坏后骨骼的钙化有何不同。如果我们能确定是什么导致慢性炎症对组织造成损害，那么我们就能开始设计控制甚至逆转这种损害的策略。这个项目将专门研究骨骼和血管，因为慢性炎症是许多疾病和病症的一个特征，但如果多（ADP核糖）确实是造成重大损害的原因，那么我们将研究慢性炎症和细胞坏死是因素的其他疾病，如阿尔茨海默病等神经退行性疾病。

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.