Role of neuraminidase activity on endothelial dysfunction in type 2 diabetes

神经氨酸酶活性对 2 型糖尿病内皮功能障碍的作用

• 批准号: 10207884
• 负责人: Luis A Martinez-Lemus
• 金额: $ 69.33万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207884
• 关键词: Ablation; Animal Model; Antioxidants; Arteries; Biochemical; Biological Availability; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell membrane; Characteristics; Cleaved cell; Clinical Trials; Data; Development; Diabetes Mellitus; Disintegrins; Endothelial Cells; Endothelium; Enzymes; Glycocalyx; Glycoproteins; Goals; Gold; Homeostasis; Human; Impairment; Inflammatory; Lead; Measures; Mediating; Membrane; Metalloproteases; Methodology; Morbidity - disease rate; Mus; Neuraminidase; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Patients; Pharmacology; Phosphatidylserines; Physiological; Plasma; Play; Process; Production; Proteoglycan; Publishing; Reactive Oxygen Species; Research; Risk Factors; Role; Sialic Acids; Signal Transduction; Structure; Testing; Therapeutic; Vasodilation; Vasodilator Agents; Work; base; endothelial dysfunction; experimental study; genetic manipulation; human subject; improved; innovation; loss of function; mechanical force; mechanotransduction; mortality; new therapeutic target; novel; prevent; response; shear stress

PROJECT SUMMARY/ABSTRACT Endothelial dysfunction is causally implicated in the development of cardiovascular disease (CVD), the main cause of death in patients with type 2 diabetes (T2D). The endothelium regulates arterial diameter and vascular homeostasis via the production of a myriad of vasoactive substances including nitric oxide (NO). NO is a powerful vasodilator produced in response to blood flow-induced shear stress, which is detected by mechanosensitive endothelial luminal structures. The glycocalyx is such a mechanosensor. It consists of a mesh of interwoven glycoproteins and proteoglycans that, when disturbed by shear stress, converts mechanical forces into biochemical signals. The appropriate result of this process, known as mechanotransduction, is endothelium-dependent flow-mediated dilation (FMD), which is considered the gold- standard physiological measure of endothelial function. Notably, impaired FMD is highly prevalent in T2D and also represents a critical component of the mechanisms that lead to CVD. However, despite the major role that reduced FMD plays in T2D-associated CVD development, the mechanisms that lead to this abnormal response are not completely known. In addition, there are currently no specific therapeutic means to alleviate impaired FMD. A central goal of this proposal is to decipher the mechanisms underlying the impairment of FMD in T2D and discover new therapeutic targets to improve it. Based on our prior work and most recent and exciting preliminary data, we propose the novel hypothesis that increased plasma neuraminidase activity degrades glycocalyx structures via activation of ADAM17 (a disintegrin and metalloproteinase-17) and promotes endothelial dysfunction in T2D. We will test our innovative hypothesis with gain- and loss-of-function pharmacological and genetic-manipulation experiments in human cultured endothelial cells and isolated arteries, in animal models of neuraminidase ablation and T2D, and in patients with T2D. Specifically, in Aim 1, using cultured endothelial cells and isolated arteries from humans, we will determine the mechanisms by which neuraminidase activity increases endothelial ADAM17 activation and impairs FMD. Subsequently, in Aim 2, we will determine the effects of neuraminidase inhibition on endothelial function in animal models and patients with T2D. We hypothesize that neuraminidase inhibition in T2D mice or humans improves FMD and overall vascular function. Our team is poised to move cardiovascular and diabetes research forward with a project that will exert a sustained, powerful impact across a number of levels of inquiry that are novel conceptually, mechanistically, methodologically, and therapeutically. Indeed, targeting neuraminidase activity holds extraordinary promise for correcting endothelial dysfunction in T2D and ultimately preventing/treating T2D- associated CVD.

项目摘要/摘要 内皮功能障碍与心血管疾病（CVD）的发展有关 2型糖尿病患者（T2D）的死亡原因。内皮调节动脉直径和 血管稳态通过产生多种血管活性物质，包括一氧化氮（NO）。不 是一种功能强大的血管扩张剂，以响应血流引起的剪切应力，这是由 机械敏感的内皮管腔结构。糖蛋白是这样的机械传感器。它由 交织的糖蛋白和蛋白聚糖的网格，当剪切应力干扰时，会转换 机械力成生化信号。此过程的适当结果，称为 机械转导，是内皮依赖性流介导的扩张（FMD），被认为是金 - 内皮功能的标准生理测量。值得注意的是，FMD受损在T2D中很普遍，并且 还代表导致CVD的机制的关键组成部分。但是，尽管有主要角色 这降低了FMD在T2D相关的CVD发展中的作用，导致这种异常的机制 响应并不完全知道。此外，目前没有具体的治疗方法来减轻 FMD受损。该提议的核心目标是破译损害损害的机制 T2D中的FMD并发现新的治疗靶标以改进它。根据我们先前的工作以及最近的工作 令人兴奋的初步数据，我们提出了增加血浆神经氨酸酶活性的新假设 通过激活ADAM17（崩解蛋白和金属蛋白酶17）和 促进T2D中的内皮功能障碍。我们将通过功能丧失和功能丧失来检验我们的创新假设 在人培养的内皮细胞中进行的药理和遗传操作实验，并分离 动脉，在神经酶消融和T2D的动物模型中，以及T2D患者。具体来说，在AIM 1中， 使用人类培养的内皮细胞和孤立的动脉，我们将确定该机制 神经氨酸酶活性增加了内皮ADAM17激活并损害FMD。随后，在AIM 2中 我们将确定神经氨酸酶抑制对动物模型和患者内皮功能的影响 与T2D。我们假设T2D小鼠或人类中的神经氨酸酶抑制作用可改善FMD和总体 血管功能。我们的团队准备将心血管和糖尿病研究转向一个项目 这将在许多概念上都是新颖的探究层面的持续，强大的影响， 机械，方法论和治疗。确实，靶向神经氨酸酶活性 在T2D中纠正内皮功能障碍的非凡承诺，并最终阻止/治疗T2D- 相关的CVD。