Project Summary
The blood-brain barrier (BBB) is a set of properties unique to central nervous system (CNS) endothelial
cells (ECs) that comprise the inner walls of blood vessels. Together, these properties greatly limit vascular
permeability to a vast majority of circulating ions, protecting the homeostasis of the CNS microenvironment. BBB
dysfunction is a key component of many neurological conditions, including multiple sclerosis (MS), stroke,
epilepsy, and traumatic brain injury (TBI). Despite the vastly different triggers of these diseases, in each case
increased vascular permeability potentiates neurological damage and clinical outcomes. Identifying common
molecular changes at the BBB across conditions could point towards a therapeutic target for reducing BBB
dysfunction. A therapeutic strategy targeting the BBB would be clinically relevant for patients suffering from
several common neurological conditions.
With this therapeutic strategy as a long-term goal, this proposal aims to investigate a novel candidate for
manipulating CNS vascular permeability: PDZ and LIM domain protein 1 (Pdlim1). In health, Pdlim1 is expressed
in more permeable peripheral ECs but not in CNS ECs. In diseases in which the BBB is disrupted, however,
preliminary data shows that Pdlim1 is highly upregulated in CNS ECs, suggesting that Pdlim1 may help regulate
barrier properties and vascular permeability. The goal of this proposal is to understand the mechanistic role of
Pdlim1 at the BBB and whether it is sufficient and/or necessary for BBB dysfunction.
While Pdlim1 has never been studied in CNS ECs or in the context of the BBB, a previous study suggests
that Pdlim1 prevents nuclear translocation of b-catenin in cancerous epithelial cells. b-catenin is a key player in
the canonical Wnt signaling pathway, a pathway shown by many groups to be crucial for BBB development and
maintenance. If Pdlim1 were able to sequester b-catenin in the cytoplasm, it could disrupt the Wnt signaling
needed for BBB maintenance. This proposal will test the hypothesis that upregulation of Pdlim1 inhibits Wnt
signaling in CNS ECs, thereby driving BBB dysfunction and vascular permeability during disease. Specifically,
Pdlim1 knockout and overexpressing transgenic mice will be used to manipulate Pdlim1 levels in order to assess
its effect on BBB integrity in disease and in health. In addition, using cell culture systems and a Wnt reporter line,
this proposal will probe whether Pdlim1 exerts its effects through the Wnt signaling pathway and will further
investigate which proteins Pdlim1 interacts with in vivo. Understanding the role of Pdlim1 at the BBB in disease
may elucidate a crucial endogenous driver of BBB dysfunction. Pdlim1 may prove to be a viable candidate for
targeting BBB disruption, a therapeutic strategy that could reduce symptom severity in many neurological
conditions including MS, stroke, epilepsy, and TBI.