Document text
Principal Investigator: Larissa A. Shimoda
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $718,982
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Pulmonary arterial hypertension (PAH) is a severely debilitating disease with no cure. Morphometric
studies revealed that the development of pulmonary hypertension is associated with robust structural
remodeling of the small pulmonary arteries, characterized by thickening of the endothelial and smooth muscle
cell layers and formation of occlusive lesions. In addition to increased proliferation and migration of vascular
cells, failure of appropriate apoptosis (i.e., apoptotic resistance) contributes to remodeling via lack of cell
turnover. Our laboratory identified a new candidate as a regulator of pulmonary arterial smooth muscle cell
(PASMC) function: aquaporins (AQPs). AQPs are a family of proteins that form transmembrane channels
which facilitate the transport of water into and out of cells. We have evidence that aquaporin 1 (AQP1), the first
family member identified, is expressed in PASMCs and pulmonary microvascular endothelial cells (PMVECs),
upregulated in a rat model of PAH and modulates susceptibility to apoptosis. Our preliminary data also indicate
that increased AQP1 protein is associated with elevated β-catenin expression, a protein that regulates
migratory, proliferative and survival responses. The mechanism by which AQP1 regulates β-catenin levels is
currently unknown; we have generated exciting data indicating a critical role for a specific region of the AQP1
C-terminal tail. This region contains a previously unrecognized putative binding site for GSK3β, an endogenous
regulator of β-catenin abundance. Based on these data, we hypothesize that in PAH PASMCs and PMVECs,
increased AQP1 levels contribute to cell growth and survival by sequestering GSK3β and reducing its
activity/nuclear localization; as a consequence, β-catenin accumulates, promoting migration and proliferation
and preventing apoptosis. The Aims of this study are to: 1) determine whether AQP1 regulates β-catenin via
binding to GSK3β; 2) identify the mechanism by which AQP1 facilitates cell growth and survival; and 3)
evaluate whether cell-specific disruption of AQP1 prevents or reverses PAH.
Terms: <AQP1 gene><Apoptosis><Apoptosis Pathway><Apoptotic><Aquaporins><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Binding Sites><Blood Vessels><Blood capillaries><C-terminal><CUL-2><Cell Adhesion><Cell Anoxia><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Hypoxia><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Nucleus><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Adhesion><Cellular Anoxia><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Hypoxia><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cellular Proliferation><Combining Site><Common Rat Strains><Complex><Cytoplasm><Data><Development><Disease><Disorder><Dissociation><Distal><Endothelial Cells><Endothelium><Epithelial Cells><Failure><Family member><Ferricytochrome c><Ferrocytochrome c><GSK-3beta><GSK-3β><Human><Hydrogen Oxide><Hypoxia><Hypoxic><Induction of Apoptosis><Intracellular Communication and Signaling><Involuntary Muscle><Ion Channel><Ionic Channels><Knowledge><Laboratories><Leiomyocyte><Lesion><Lung><Lung Respiratory System><Mediating><Membrane Channels><Modeling><Modern Man><Molecular><Molecular Interaction><Muscle><Muscle Tissue><Mutate><Nuclear><Nuclear Translocation><Nucleus><Oxygen Deficiency><PRO2286><Pathology><Pathway interactions><Patients><Permeability><Phenotype><Phosphorylation><Predisposition><Prevention><Programmed Cell Death><Proliferating><Protein Family><Protein Phosphorylation><Proteins><Publishing><Pulmonary Hypertension><Pulmonary arterial remodeling><Rat><Rats Mammals><Rattus><Reactive Site><Regulation><Reporting><Repression><Resistance><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stimulus><Subcellular Process><Susceptibility><Tail><Testing><Up-Regulation><Upregulation><Vascular Endothelial Cell><Vascular remodeling><Water><Water Channel Proteins><aquaporin 1><beta catenin><biological signal transduction><capillary><cell growth><cell motility><cytochrome c><developmental><distal pulmonary artery remodeling><experiment><experimental research><experimental study><experiments><glycogen synthase kinase 3 beta><glycogen synthase kinase 3β><improved><in silico><insight><lung arterial remodeling><lung artery blood pressure><lung microvascular endothelial cells><lung vascular endothelial cells><migration><mortality><muscular><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pressure in pulmonary arteries><prevent><preventing><protein function><protein protein interaction><pulmonary><pulmonary arterial blood pressure><pulmonary arterial endothelial cell><pulmonary arterial hypertension><pulmonary arterial pressure><pulmonary arterioles remodeling><pulmonary artery endothelial cell><pulmonary artery hypertension><pulmonary artery pressure><pulmonary artery remodeling><pulmonary artery systolic pressure><pulmonary microvascular endothelial cells><pulmonary vascular endothelial cells><renal epithelium><resistant><response><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><small pulmonary artery remodeling><social role><therapeutic target><vascular><water channel><water transporter><β-catenin>