Dedicator of Cytokinesis 2 (DOCK2) in Aortic Valve Calcification

About This Grant

Summary/Abstract Calcific aortic valve disease (CAVD) is a progressive and life-threatening condition that currently lacks effective pharmacological therapies. Aortic valve calcification (AVC), the central pathological hallmark of CAVD, leads to valve stiffening, reduced cardiac output, and ultimately aortic stenosis, contributing significantly to cardiovascular morbidity and mortality. Despite the clinical burden of AVC, the molecular mechanisms driving calcification remain poorly defined, and no FDA-approved medical therapies exist to halt or reverse disease progression. Key pathological processes in AVC include the osteogenic differentiation of valve interstitial cells (VICs) and the endothelial-to-mesenchymal transition (EndoMT) of valvular endothelial cells (VECs). Emerging evidence identifies Dedicator of Cytokinesis 2 (DOCK2), a guanine nucleotide exchange factor traditionally associated with immune cell signaling, as an important regulator of aortic valve cellular processes. Preliminary data demonstrate that DOCK2 is upregulated in human calcified valves and localizes to both VICs and VECs. DOCK2 deficiency in mouse models significantly reduces AVC, and in vitro knockdown of DOCK2 in VICs and ECs suppresses osteogenic differentiation and EndoMT, respectively. Mechanistic studies implicate two distinct signaling axes: DOCK2 promotes VIC osteogenesis via the PI3K/Akt/GSK3β/β-catenin pathway, and it drives EndoMT through ROS-mediated ERK signaling. The objective of this proposal is to elucidate the cell- specific mechanisms by which DOCK2 contributes to AVC and to evaluate the therapeutic potential of a small molecule DOCK2 inhibitor, cholesterol sulfate. Our central hypothesis is that DOCK2 drives AVC by independently promoting VIC osteogenic reprogramming and EC EndoMT through distinct but targetable signaling pathways. This will be tested through three specific aims: Aim 1 will define the role of DOCK2 in VIC- mediated AVC and determine its signaling mechanism; Aim 2 will establish the contribution of DOCK2 to EndoMT in VECs and elucidate the downstream ROS-ERK pathway; Aim 3 will test whether pharmacologic inhibition of DOCK2 with cholesterol sulfate can prevent or reverse AVC in vivo. The successful completion of this project will identify DOCK2 as a critical molecular driver of AVC, uncover distinct mechanistic pathways in VICs and VECs, and validate a novel small molecule inhibitor as a therapeutic candidate. These studies are expected to significantly advance our understanding of CAVD pathogenesis and provide a foundation for developing targeted, non-surgical interventions to treat or reverse aortic valve calcification.