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.
The proposed project will investigate the role of PDZ and LIM domain protein 1 (Pdlim1) in driving central nervous system (CNS) vascular permeability during disease. The results of this project will deepen the field?s understanding of the molecular mechanisms underlying blood-brain barrier dysfunction, a central component of a wide range of diseases and injuries including multiple sclerosis (MS), stroke, epilepsy, and traumatic brain injury (TBI). The data produced by the proposed experiments may help elucidate a therapeutic strategy for targeting BBB disruption, thereby mitigating symptoms of many common neurological conditions.
