Development & Maintenance of the BBB
What are the cellular and molecular mechanisms that govern development and maintenance of the BBB?
We are interested in identifying key signaling pathways that regulate formation of the BBB in order to repair BBB function in CNS diseases in which the barrier breaks down.
We have found that the Wnt/beta-catenin pathway plays an important role in regulating both CNS angiogenesis and some properties of the barrier. We have identified a novel inhibitor of this pathway named Apcdd1 that is expressed in CNS endothelial cells when they acquire their barrier properties during development. We are currently investigating the roles of Apcdd1 in CNS angiogenesis and blood-brain barrier development.
We are also interested in understanding how tight junctions between endothelial cells in the CNS develop and mature during BBB formation. We have developed proteomic discovery platforms for: a) identifying novel junctional proteins important for barrier development and function; and b) potential structural modifications of tight junction proteins that underlie CNS diseases exhibiting reduced barrier function.
- Cottarelli A, Shahriar S, Arac A, Glendinning M, Tuohy MC, Prochilo G, Neal JB, Edinger AL, Agalliu D. Rab7a activation promotes degradation of select tight junction proteins at the blood-brain barrier after ischemic stroke. bioRxiv 2023 Aug 29;555373. doi: https://doi.org/10.1101/2023.08.29.555373
- Biswas S, Shahriar S, Bachay G, Arvantitis P, Brunken WJ, Agalliu D. Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling. bioRxiv 2023 Jul 10;548410. doi: https://doi.org/10.1101/2023.07.10.548410
- Biswas S, Shahriar S, Giangreco NP, Arvanitis P, Winkler M, Tatonetti NP, Brunken WJ, Cutforth T, Agalliu D. Mural Wnt/β-catenin signaling regulates Lama2 expression to promote neurovascular unit maturation. Development. 2022 Sep 1;149(17):dev200610. doi: 10.1242/dev.200610.
- Cottarelli A, Corada M, Beznoussenko GV, Mironov AA, Globisch MA, Biswas S, Huang H, Dimberg A, Magnusson PU, Agalliu D, Lampugnani MG, Dejana E. (2020) Fgfbp1 promotes blood-brain barrier development by regulating collagen IV deposition and maintaining Wnt/β-catenin signaling. Development Aug 24;147(16):dev185140.
- Biswas S, Cottarelli A, Agalliu D. (2020) Neuronal and glial regulation of CNS angiogenesis and barriergenesis.
- Mazzoni J, Smith JR, Shahriar S, Cutforth T, Ceja B, Agalliu D. (2017) The Wnt Inhibitor Apcdd1 Coordinates Vascular Remodeling and Barrier Maturation of Retinal Blood Vessels. Neuron. Dec 6;96(5):1055-1069.e6.
Cellular and molecular mechanisms of blood-retina barrier formation and maintenance.
In the Agalliu laboratory, Rishi primarily focuses on the development and maintenance of the blood-retina barrier. In one project, Rishi studies the role of canonical Wnt signaling, specifically the canonical Wnt inhibitor Apcdd1, in these processes. Although canonical Wnt signaling has been shown to regulate barriergenesis in retinal vessels, the precise downstream cellular and molecular mechanisms by which that is achieved is unclear. This study aims to elucidate those unanswered questions, with the ultimate goal of finding novel therapeutic approaches to treat neurovascular disorders.
A second project examines how retinal neuronal activity affects the blood-retina barrier formation. This is one area of neurovascular coupling that has not been explored previously. These studies have the potential to uncover new mechanistic insights into the interdependency of neural and vascular development.