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Principal Investigator: Yanning Rui
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $370,651
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
An intracranial aneurysm (IA) is a bulge or ballooning of the cerebral artery due to weakness in the blood
vessel wall. IA rupture causes subarachnoid hemorrhage (SAH), the most life-threatening form of stroke.
However, the molecular mechanisms underlying IA pathogenesis are poorly understood, which greatly
impedes the identification of therapeutic targets. To date, no pharmacological treatment is available for
IA except for invasive surgical options, such as surgical clipping and endovascular coiling, both of which
are generally associated with high hospitalization costs. Our long-term goal is to elucidate the molecular
mechanisms of IA and develop new therapeutic avenues for this devastating disease. The overall
objective in this application is to determine the role of selective autophagy of endothelial focal adhesion
(FA) in cerebrovascular integrity and IA formation and progression. The central hypothesis is that p62-
VASP interaction is a critical cargo recognition mechanism for selective autophagy of FA (FA-phagy) in
endothelial cells, which impairs cerebrovascular integrity and contributes to IA formation and progression.
The central hypothesis will be tested in two specific aims: 1) dissect the molecular mechanisms of FA-
phagy in endothelial cells; and 2) determine the role of endothelial FA-phagy in cerebrovascular integrity
and IA formation and progression. Our proposal is innovative, because we are the first to identify p62-
VASP interaction as a novel cargo recognition mechanism for endothelial FA-phagy, and provide
endothelial FA-phagy as a novel pathogenic mechanism for IA. The proposed research is significant
because we connect selective autophagy to cerebrovascular integrity, which will not only add cutting-
edge knowledge to the selective autophagy field but also provide anti-FA-phagy strategy as a novel
therapy for IA disease or potentially for many other diseases that exhibit the loss of vascular integrity.
Terms: <Adhesion Plaques><Affect><Affinity><Animal Model><Animal Models and Related Studies><Apoplexy><Area><Assay><Autophagocytosis><Binding><Bioassay><Biological Assay><Blood Vessels><Brachydanio rerio><Brain Aneurysms><Brain Vascular><Brain Vascular Accident><Cause of Death><Cell Body><Cell-Extracellular Matrix><Cell-Matrix Adherens Junctions><Cells><Cerebral Arterial Circle><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Circle of Willis><Complex><Danio rerio><Data><Death><Degradation Pathway><Degradative Pathway><Development><Digestion><Disease><Disorder><ECM><Endothelial Cells><Endothelium><Exhibits><Extracellular Matrix><Focal Adhesions><Focal Contacts><Generalized Growth><Genes><Genetic><Goals><Growth><Health><Hospital Costs><Hospitalization cost><Impairment><Incidence><Intracranial Aneurysm><KO mice><Kinetics><Knock-out Mice><Knockout Mice><Knowledge><Life><Link><Mediating><Mice><Mice Mammals><Mission><Molecular><Molecular Interaction><Morphology><Murine><Mus><NIH><Names><National Institutes of Health><Null Mouse><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pharmacological Treatment><Phosphorylation><Play><Process><Protein Phosphorylation><Public Health><Receptor Protein><Research><Resolution><Role><Rupture><Ruptured Aneurysm><Series><Staining method><Stains><Stroke><Subarachnoid Hemorrhage><Surgical><Surgical Clips><Surgical Interventions><Surgical Procedure><System><Testing><Time><Tissue Growth><United States National Institutes of Health><VASP><Variant><Variation><Vascular Permeabilities><Work><Zebra Danio><Zebra Fish><Zebrafish><autophagy><brain attack><burden of disease><burden of illness><cerebral artery><cerebral vascular><cerebral vascular accident><cerebro-vascular><cerebrovascular><cerebrovascular accident><developmental><disability><disease burden><experiment><experimental research><experimental study><experiments><gain of function><improved><innovate><innovation><innovative><knock-down><knockdown><model of animal><mouse model><murine model><name><named><naming><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><ontogeny><preservation><prevent><preventing><receptor><receptor binding><receptor bound><resolutions><shear stress><single molecule><social role><stroke patient><stroked><strokes><superresolution microscopy><surgery><therapeutic target><vascular><vasodilator-stimulated phosphoprotein>