Summary
This research project investigates the synergistic influences of structural and energetic compromise on blood-brain barrier (BBB) function, particularly focusing on mitochondrial energetics as a potential therapeutic target for neuropsychiatric disorders like 22q11.2 deletion syndrome (22qDS).
What they want
Aim 1 will investigate whether mitochondrial weakness and the presence of schizophrenia (SZ) in 22qDS extends to iPSC-derived BBB-like cells (iBBB) and examine if interventions that enhance mitochondrial energetics improve BBB function in both 22qDS iBBB and 22qDS model mice. Aim 2 will use a reduced system, outside of the 22qDS context, to study whether OXPHOS compromise synergizes with CLDN5 haploinsufficiency to generate greater BBB insufficiency, testing whether crossing mice heterozygous for claudin-5 in the BBB with those lacking the mitochondrial-DNA encoded gene ND6 will have exacerbated BBB dysfunction, and whether enhancing mitochondrial energetics pharmacologically will rectify BBB dysfunction in neurovascular selective claudin-5 +/- mice.
Technical requirements
- Induced pluripotent stem cell (iPSC)-derived BBB-like cells (iBBB)
- 22qDS model mice
- Mice heterozygous for claudin-5 in the BBB
- Mice lacking the mitochondrial-DNA encoded gene ND6
- Pharmacological interventions to enhance mitochondrial energetics
