Justin Lengfeld is a Ph.D. candidate in Dritan Agalliu’s lab in the department of Developmental and Cell Biology with a focus on understanding cell biological mechanisms of blood-brain barrier impairment in neuroinflammatory conditions such as multiple sclerosis, where blood-brain barrier breakdown contributes to immune cell infiltration and disease progression. MS is an immune-mediated disease in which T cells become activated towards myelin following exposure to unknown antigens. Abnormalities in endothelial cells (ECs) and an increase in blood-brain barrier (BBB) permeability in MS have been considered secondary to inflammation, however BBB breakdown occurs early during MS pathogenesis. The barrier properties of ECs are mediated by three mechanisms: 1) the presence of tight junctions (TJs) that prevent diffusion of small molecules between ECs (paracellular pathway); 2) very few endocytotic vesicles (caveolae) that transcytose slowly, thereby reducing transport of large molecules within the brain endothelium (transcellular pathway); and 3) transporters that shuttle only selected molecules between the blood and the brain. It is known that the BBB degrades prior to MS relapses and is subsequently repaired during the remission of symptoms. Induction of barrier features such as tight junction (TJ) expression, the low rate of transcytosis and the presence of certain transporters require Wnt/β-catenin signaling. To date, however, no studies have examined if Wnt/β-catenin signaling is activated in CNS ECs during disease progression.
Experimental Autoimmune Encephalomyelitis (EAE) is a mouse model that recapitulates several defining features of human MS, including barrier breakdown and infiltration of autoreactive T cells into the CNS. Through the use of Wnt/β-catenin reporter mice as well as evaluating downstream gene transcription of Wnt/β-catenin pathway targets, Justin has shown that Wnt/β-catenin signaling is upregulated in CNS ECs during EAE progression. This data has led to the creation of novel transgenic mice to allow for the manipulation of Wnt/β-catenin signaling in ECs during EAE progression. These mice will be used to define the function of the Wnt/β-catenin signaling during EAE and the effect it has on BBB integrity. In addition to this project, Justin is also interested in examining post-translational modifications that TJ molecules undergo during EAE progression and how this affects BBB integrity.