Saturday, November 23, 2024
11/23/2024
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.
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