The blood-brain barrier (BBB) acts as a signaling and transport interface between the blood and brain. The BBB begins to form early in embryonic development as the mesoderm-derived vasculature invades the immature central nervous system (CNS) and begins to gain BBB characteristics such as tight junctions and a lack of fenestrae. After further maturation, the adult BBB, with its very low permeability and a wealth of molecular transport systems, is maintained by interactions with supporting cells of the neurovascular unit. While recent studies have indicated the importance of Wnt/beta- catenin, angiotensin II, and sonic hedgehog signaling on BBB development, many BBB attributes remain unaffected when these pathways are disrupted. Thus, our understanding of the molecular mechanisms underpinning BBB formation is incomplete, and in this proposal we aim to further examine the mechanisms that regulate BBB development and maintenance. Recently, we have identified nuclear receptors RXRalpha and PPARdelta as two potential regulators of BBB function. As described in the preliminary data, these receptors are specifically expressed at the BBB compared to peripheral endothelia, receptor agonists can drive BBB phenotypes in endothelial cells differentiated from human pluripotent stem cells (hPSC-derived BMECs), and endothelial-specific deletion of these receptors results in partial neonatal lethality (RXRalpha) and a leaky BBB (PPARdelta) in vivo. Thus, we hypothesize that the nuclear receptors RXRalpha and PPARdelta are crucial regulators of BBB development and maintenance. To test our hypothesis, we will evaluate the in vivo BBB phenotype upon embryonic and postnatal endothelial-specific deletion of RXRalpha and PPARdelta in mice. The molecular mechanisms governed by RXRalpha and PPARdelta activation will be evaluated using the differentiation process of hPSC-derived BMECs as a window to human BBB induction and maintenance. Finally, potential synergy on BBB formation arising from RXRalpha and PPARdelta co-activation will be assessed in vivo and in vitro. Understanding the regulators of BBB induction could yield many new insights regarding fetal brain disease. Furthermore, knowledge of the barrier-genesis and barrier maintenance pathways could open new avenues for restoring BBB function in debilitating neurological disease.

Public Health Relevance

Understanding the developmental program of the BBB will assist our understanding of how this critical vascular interface functions in protecting the CNS and how dysfunction leads to neurological disease. A detailed understanding of the mechanisms guiding BBB induction and maintenance could potentially be leveraged for the restoration of BBB function in patients suffering from neurological diseases such as stroke and multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS083688-01
Application #
8557312
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Bosetti, Francesca
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$385,660
Indirect Cost
$112,047
Name
University of Wisconsin Madison
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Wilson, Hannah K; Canfield, Scott G; Shusta, Eric V et al. (2014) Concise review: tissue-specific microvascular endothelial cells derived from human pluripotent stem cells. Stem Cells 32:3037-45
Lippmann, Ethan S; Al-Ahmad, Abraham; Azarin, Samira M et al. (2014) A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 4:4160