Thursday, May 9, 2024
5/9/2024
Summary Neuroinflammatory processes are increasingly associated with neuropsychiatric disorders and diseases. The blood-brain barrier (BBB) is a critical modulator of peripheral inflammatory influences on brain development and function. Co-PIs Jorge Alvarez, a neuroimmunologist with expertise in the BBB, and Stewart Anderson, a developmental neurobiologist with expertise in mechanisms of neuropsychiatric disorders, have recently demonstrated that the BBB is compromised in a relatively common genetic cause of neuropsychiatric illness, the 22q11.2 deletion syndrome (22qDS). While this finding in induced pluripotent stem cell (iPSC)-derived BBB-like cells (iBBB) and in 22qDS mice was initially ascribed at least partially to haploinsufficiency of the BBB-enriched tight junction protein claudin-5, work from the Anderson lab and others has also demonstrated that 22qDS is associated with mitochondrial energetic compromise in various cell types. Since mitochondrial energetics are also necessary for optimal BBB function, the PIs initiated experiments to determine whether mitochondrial energetics of the BBB are compromised in 22qDS, whether this compromise is likely to influence BBB dysfunction in this disorder, and whether correction of mitochondrial weakness improves BBB dysfunction in 22qDS. Remarkably, our preliminary data suggest that the answer to all three possibilities is yes. Here, we propose to study the synergistic influences of structural and energetic compromise on BBB function. As we have previously found in iPSC-derived neurons and transformed blood cells that the presence of 22qDS with schizophrenia (SZ) is associated with weaker mitochondrial energetics than 22qDS without SZ or non-deleted controls, in Aim 1 we will assess whether this association of mitochondrial weakness and the presence of SZ in 22qDS extends to iBBB cells. We will also examine whether interventions that enhance mitochondrial energetics improve BBB function, both in the 22qDS iBBB, and in 22qDS model mice. In Aim 2 we will use the more reduced system of mice heterozygous only for claudin-5, and selectively in the BBB, that have been shown to have a moderate neurovascular deficit. We will test whether crosses of these mice with those lacking the mitochondrial-DNA encoded gene ND6 will have exacerbated BBB dysfunction relative to each mutation alone. We will also test whether enhancing mitochondrial energetics pharmacologically will rectify BBB dysfunction in the neurovascular selective claudin-5 +/- mice. In sum, the mitochondrial influence on BBB function is an underexplored area of study. Since these influences are therapeutically targetable and since the BBB's influence on neuroinflammation and brain health is increasingly appreciated, this proposal could lead to important novel therapeutics both within and beyond the 22qDS context.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
