Abstract
The central nervous system (CNS), comprised of the brain, spinal cord and retina, is the most
vascularized organ system in the human body. Neurons and glial cells closely contact blood
vessels and communicate with vascular endothelial cells and pericytes to control normal CNS
development and physiology. Blood vessel dysfunction occurs in multiple CNS diseases,
including developmental brain disorders, retinal deficits, and age-related neurodegeneration.
We understand surprisingly little about mechanisms that regulate normal CNS vascular
development and physiology or how these events go awry during disease pathogenesis. To
characterize new and potentially targetable factors that control blood vessel morphogenesis in
the developing CNS, we queried open-source databases to identify genes with putative roles in
vascular endothelial cell growth, differentiation and sprouting. These efforts have led to the
current project focused on Prnd, a member of the prion gene family that is expressed in the
CNS vascular endothelium. We present a substantial amount of data that bolster our working
hypothesis that glycophosphatidylinositol (GPI)-linked Prnd activates endothelial cell signaling
pathways to regulate angiogenesis and blood vessel permeability in the brain and retina.
Furthermore, we propose that abnormal Prnd expression and function contributes to brain and
retinal blood vessel pathologies. To test our hypotheses, we will (1) utilize biochemical
strategies and high-resolution cell imaging methods to analyze Prnd-dependent signaling
pathways that promote endothelial cell differentiation, growth and migration; (2) analyze roles
for Prnd in developmental and pathological CNS angiogenesis; and (3) identify and characterize
cues in the CNS microenvironment that promote Prnd expression and functions in angiogenic
endothelial cells. In summary, these experiments will reveal novel functions for Prnd in
regulating CNS blood vessel morphogenesis and may identify new targets for therapeutically
inhibiting pathological angiogenesis in the CNS.