Mechanisms regulating blood vessel formation, stabilization, and blood flow sensing during development and disease
My lab is broadly interested in how blood vessels form and stabilize, and how changes in these processes affect the homeostasis of the tissues around them. In particular, we are interested in how improper networking and stabilization of the vasculature leads to the onset of neurodegenerative disorders. To address these questions, we utilize the zebrafish, along with sophisticated in vitro 3D modeling assays of the vasculature. Zebrafish, as a vertebrate model organism, offer a number of advantages that make it an ideal system to study the interactions between vascular and neuronal dysfunction- including proper embryonic growth/development for 4-5 days in the complete absence of normal blood flow, optical clarity for longitudinal imaging, and genetic/experimental accessibility, including fluorescent transgenic reporter constructs marking virtually every cell type in the embryo. We recently carried out a forward genetic screen that identified a number of new zebrafish mutants that demonstrated vascular abnormalities, including intercranial hemorrhage and vessel mispatterning defects. Proteomic analysis from isolated endothelial cells of mutant and wild type siblings has revealed that many of the mutant phenotypes are linked to mis-regulated endosomal/lysosomal trafficking pathways. While this in and of itself is interesting to study, we also identified a number of strong, positive hit proteins in our mutant endothelial cells that directly relate to neurodegenerative/cognitive disorders, including APP/amyloid beta (Alzheimer’s related), PARK7 (Parkinson’s related), FXR1/FXR2, NOVA2 (Fragile-X related), ATN1 (Dentatorubral- Pallidoluysian Atrophy Related), among a host of others. The lab is now undertaking studies to determine how defects in vascular function and vesicular trafficking are leading to the upregulation of these neuronal disorder related proteins in the endothelium, and what the consequences of this regulation are in the onset of neurodegenerative disorders.