Hyperglycemia and MicroRNA Dysregulation of Inflammation in Atherosclerosis

这项提案的目的是了解为什么糖尿病患者在糖尿病患者中斑块的形成更快， 动脉这个问题通常被称为“动脉粥样硬化”，它直接导致几种类型的动脉粥样硬化。 严重的心血管疾病导致许多残疾和过早死亡。的一大原因 糖尿病患者在生命早期发展严重的动脉粥样硬化是因为高血糖， 称为“高血糖症”。高血糖症增强动脉粥样硬化的确切原因尚不清楚。不幸的是， 对糖尿病小鼠的研究表明，高血糖会加速动脉粥样硬化， 胆固醇水平。因为这种增加的血液胆固醇本身会加速动脉粥样硬化， 糖尿病患者的血液中胆固醇并不总是增加，高血糖如何导致更严重的 动脉粥样硬化仍然没有完全了解。在我们实验室进行的工作导致了一种新的菌株， 糖尿病高血糖症不会进一步增加血液胆固醇水平的基因工程小鼠。 我们对这些糖尿病小鼠的最新研究表明，高血糖通过增加 在血液和动脉壁中积累的激活的免疫细胞的数量。我们还发现， 高血糖改变了一类称为microRNA的细胞内分子的表达， 免疫细胞中的基因程序使它们更活跃，更容易引起炎症。因为一个 免疫系统激活会加速动脉粥样硬化，我们的发现可以部分解释临床 观察糖尿病患者动脉粥样硬化的加速和侵袭性形式。因此 我们的拨款提案的中心焦点将是揭示高血糖症如何改变微RNA水平， 免疫细胞和它们的祖细胞驱动它们的激活，从而加速动脉粥样硬化。 在我们的第一个目标中，我们将定义哪些microRNA在血液中的免疫细胞及其祖细胞中发生了改变， 脾脏和动脉粥样硬化病变的糖尿病小鼠，以及这如何改变他们的细胞活化。我们将研究 免疫细胞暴露于高水平的葡萄糖，以测试增加的细胞氧化应激是否是导致 降低microRNA水平。我们还将确定哪些酶负责这些影响。 在我们的第二个目标中，我们将测试增加免疫细胞中的抗氧化活性是否可以克服 高血糖维持正常的microRNA水平，从而防止免疫细胞活化， 糖尿病小鼠的动脉粥样硬化。我们还将测试免疫细胞中选择的microRNA的强制表达是否 可克服高血糖的影响，减轻糖尿病小鼠的炎症和动脉粥样硬化。我们将 也测试这些方法是否可以与降低血糖结合来控制糖尿病动脉粥样硬化。我们 这些发现可以为糖尿病患者和尚未发展为糖尿病的人提供急需的新治疗方法 基于操纵和使用microRNA来控制糖尿病动脉粥样硬化， 尽管有广泛可用的降低血糖和血脂的治疗方法，但严重的心血管疾病仍然存在。

The goal of this proposal is to understand why people with diabetes develop a more rapid build-up of plaque in arteries. This problem is commonly called “atherosclerosis” and it is directly responsible for several types of serious cardiovascular diseases that cause numerous disabilities and premature death. A major reason why diabetic individuals develop severe atherosclerosis early on in life is because of high blood sugar that is also called “hyperglycemia”. Exactly why hyperglycemia enhances atherosclerosis is not known. Unfortunately, studies of diabetic mice in which hyperglycemia accelerates atherosclerosis also led to increased blood cholesterol levels. Because such added blood cholesterol can itself accelerate atherosclerosis, and because diabetic humans do not always have increased blood cholesterol, how hyperglycemia causes more severe atherosclerosis remains incompletely understood. Work performed in our laboratory led to a new strain of genetically engineered mice in which diabetic hyperglycemia does not further increase blood cholesterol levels. Our latest studies of these diabetic mice reveal that hyperglycemia accelerates atherosclerosis by increasing the number of activated immune cells that accumulate in the blood and the artery wall. We also uncovered that hyperglycemia alters the expression of a class of intracellular molecules called microRNA that can regulate genetic programs in immune cells making them more active and prone to cause inflammation. Because an activated immune system is known to accelerate atherosclerosis, our findings could in part explain clinical observations of accelerated and aggressive forms of atherosclerosis among diabetic individuals. Therefore, the central focus of our grant proposal will be to uncover how hyperglycemia acts to alter microRNA levels in immune cells and their progenitors to drive their activation and thereby accelerate atherosclerosis. In our First Aim we will define which microRNA are altered in immune cells and their progenitors in the blood, spleen and atherosclerotic lesions of diabetic mice, and how this alters their cellular activation. We will study immune cells exposed to high levels of glucose to test if increased cellular oxidative stress is responsible for reducing microRNA levels. We will also identify which enzymes are responsible for these effects. In our Second Aim we will test if increasing an anti-oxidant activity in immune cells can overcome effects of hyperglycemia to maintain normal microRNA levels and thereby prevent immune cell activation and atherosclerosis in diabetic mice. We will also test if a forced expression of select microRNA in immune cells can overcome effects of hyperglycemia to reduce inflammation and atherosclerosis in diabetic mice. We will also test if these approaches can be combined with glucose lowering to control diabetic atherosclerosis. Our findings could provide much needed new treatments to diabetic individuals and those yet to develop diabetes based on the manipulation and use of microRNA to control diabetic atherosclerosis that remains a major cause of serious cardiovascular diseases despite widely available therapies that reduce blood glucose and lipids.