Hyperglycemia and MicroRNA Dysregulation of Inflammation in Atherosclerosis

这项提案的目的是为了了解为什么糖尿病患者会在 动脉。这种问题通常被称为“动脉粥样硬化”，它直接导致几种类型的 导致大量残疾和过早死亡的严重心血管疾病。一个主要原因是 糖尿病患者在生命早期就会患上严重的动脉粥样硬化，这也是因为高血糖 称为“高血糖症”。高血糖导致动脉粥样硬化的确切原因尚不清楚。不幸的是， 高血糖加速动脉粥样硬化的糖尿病小鼠的研究也导致血液增加 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，而且因为 糖尿病人并不总是有血胆固醇升高，高血糖如何引起更严重 动脉粥样硬化仍未完全了解。我们实验室的工作导致了一种新的菌株 基因工程小鼠的糖尿病高血糖不会进一步增加血液胆固醇水平。 我们对这些糖尿病小鼠的最新研究表明，高血糖通过增加 积聚在血液和动脉壁中的激活免疫细胞的数量。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，这种分子可以调节 免疫细胞中的遗传程序使它们更活跃，更容易引起炎症。因为一个 已知激活的免疫系统会加速动脉粥样硬化，我们的发现可以部分解释临床 糖尿病患者中加速和侵袭性动脉粥样硬化的观察。因此， 我们拨款提案的中心焦点将是揭示高血糖如何作用于改变脑内microRNA水平。 免疫细胞及其前体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变化， 糖尿病小鼠的脾和动脉粥样硬化病变，以及这如何改变它们的细胞活性。我们会研究 暴露在高水平葡萄糖下的免疫细胞，以测试细胞氧化应激是否增加 降低microRNA水平。我们还将确定哪些酶对这些影响负责。 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剂活性是否可以克服 高血糖以维持正常的microRNA水平，从而防止免疫细胞激活和 糖尿病小鼠的动脉粥样硬化。我们还将测试选择的microRNA在免疫细胞中的强制表达 能克服高血糖的影响，减轻糖尿病小鼠的炎症和动脉粥样硬化。我们会 还要测试这些方法是否可以与降糖相结合来控制糖尿病动脉粥样硬化。我们的 这一发现可能会为糖尿病患者和尚未发展成糖尿病的患者提供急需的新疗法。 基于对microRNA的操纵和使用来控制糖尿病动脉粥样硬化，这仍然是一个主要原因 尽管有广泛可用的降低血糖和血脂的治疗方法，但严重心血管疾病的风险仍然很高。

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.