R01HL151384

Targeting ADAM17 Activity for Correction of Vascular Insulin Resistance in Type 2 Diabetes - Project Summary/Abstract

Vascular insulin resistance is a hallmark of type 2 diabetes (T2D), and its primary consequence is the dampening of insulin-induced vasodilation. In T2D, reduced insulin-stimulated vasodilation and blood flow to tissues such as skeletal muscle significantly limit glucose uptake and contribute to impaired glucose control. To develop therapeutic strategies aimed at improving glycemic control and protecting against cardiovascular disease, it is crucial to have a detailed understanding of the precipitating factors and mechanisms underlying the defects in vasodilator actions of insulin.

Based on our prior work and most recent and exciting preliminary data, we propose the novel hypothesis that ADAM17-mediated shedding of the insulin receptor alpha (IRA) from endothelial cells impairs insulin-stimulated vasodilation in T2D. We further propose that the increased activity of endothelial ADAM17 is attributed to protein kinase C (PKC) activation and subsequent externalization of phosphatidylserine (PS) to the outer leaflet of the cell membrane, which guides ADAM17 to its targeted substrates. As exogenous PS is a competitive inhibitor of ADAM17 sheddase activity, we will also determine the efficacy of oral administration of PS for restoring vascular insulin sensitivity in T2D patients.

We will test our innovative hypotheses with gain- and loss-of-function genetic manipulation experiments in human cultured endothelial cells, in isolated resistance arteries harvested from patients undergoing abdominal surgery, and in patients with T2D. Experimental results will determine the role of PS externalization-ADAM17 activation-IRA shedding as a mechanism impairing the vasodilatory actions of insulin in T2D.

Specifically, in Aim 1, we will determine the mechanism by which PKC causes the externalization of PS and whether PS externalization is needed for PKC-dependent activation of ADAM17 in endothelial cells. Next, in Aim 2, we will determine the role of ADAM17 activity in IRA shedding and subsequent impairment of insulin-stimulated vasodilation in T2D. Finally, in Aim 3, we will perform a randomized double-blind clinical trial to determine the therapeutic efficacy of oral administration of the competitive inhibitor of ADAM17 sheddase activity, PS, on insulin-stimulated leg blood flow in patients with T2D.

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, this proposal represents a paradigm shift from our current mechanistic understanding of vascular insulin resistance. Targeting ADAM17 activation holds extraordinary promise for correcting vascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular diseases.

University Of Missouri System

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Columbia, Missouri 652112005 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-19-055)

Amendment Since initial award the total obligations have increased 455% from $611,483 to $3,391,982.