The goal of this supplemental grant is to extend the parent grant “Redox Regulation of Cu importer CTR1 in Angiogenesis” to propose a novel link between copper (Cu) metabolism, reactive oxygen species (ROS) signaling and angiogenesis with Alzheimer's disease (AD)/Vascular Contributions to Cognitive Impairment and Dementia (VCID), which is orchestrated by the Cu uptake transporter CTR1. ROS and Cu, an essential micronutrient and redox metal, are involved in angiogenesis, but their relationship is poorly understood. Cysteine sulfenic acid (Cys-OH) formation is a key initial event in ROS signaling. Cellular Cu entry is mainly via CTR1 which possess one cytosolic Cys189 at the highly conserved HCH190 triad in the C-terminus. Our parent grant focused on the role of CTR1 in ROS-dependent VEGFR2 signaling and angiogenesis in endothelial cells and post-ischemic neovascularization. Intriguingly, oxidative stress and cerebral hypoperfusion play an important role in pathogenesis of AD/VCID by regulating angiogenesis. Excess angiogenesis results in enhanced BBB permeability and amyloid (A) accumulation in brain/vessels, which contribute to neurovascular dysfunction and AD/VCID pathology. Furthermore, Cu plays an important role in AD/VCID pathology: However, the mechanics link between Cu metabolism, ROS, and angiogenesis involved in pathogenesis of AD/VCID and role of Cu transport proteins in this process are entirely unknown. Preliminary Data suggest that CTR1 protein expression was significantly upregulated in the brain of mouse models of AD and human AD patients. Together with previous reports, this supplemental grant will test the novel hypothesis that Cu uptake transporter CTR1 upregulation drives cerebral angiogenesis and BBB permeability via hyperactivation of VEGFR2 signaling in a ROS- and Cu-dependent manner, leading Aaccumulation and neurovascular dysfunction in AD/VCID. Aim 1 will characterize the CTR1 expression, Cu and ROS levels, VEGFR2 signaling and examine if CTR1 is oxidized in brain of AD/VCID. Aim 2 will determine if CTR1 promotes ROS- and Cu-dependent cerebral angiogenesis and BBB permeability, which contributes to pathogenesis in brain of AD/VCID. We propose that common mechanisms for Parent and Supplemental grants includes the ROS-CTR1 Cys oxidation- VEGFR2 signaling-angiogenesis axis, which is important for therapeutic angiogenesis (Parent grant), while its excess activation with A accumulation contributes to pathological angiogenesis/neurovascular dysfunction/dementia (Supplemental grant). We will have common reagents and approach between two projects, including newly developed inducible EC-specific Ctr1-/- mice and CRISPR/Cas9-generated CTR1 Cys oxidation-defective knock-in mutant mice; highly innovative ICP-Mass Spec and X-ray fluorescence microscopy which analyze the Cu distribution/content in brain, which are available from new collaborators with expertise on AD/VCID at our university. Our proposal will provide novel insights into Cu importer CTR1 as a potential therapeutic target for AD/VCID as well as ischemic cardiovascular diseases.
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