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Mitochondrial influences on blood brain barrier function and neuropsychiatric illness

Award Number: R01MH134893
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Mitochondrial influences on blood brain barrier function and neuropsychiatric illness - Neuropsychiatric disorders are increasingly associated with neuroinflammatory processes. The blood-brain barrier (BBB) is a critical modulator of peripheral inflammatory influences on brain development and function. 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 model mice was initially ascribed mainly 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 strongly suggest that all three scenarios are true. If so, BBB energetics could be an underexplored therapeutic target for neurodevelopmental and neurodegenerative disorders that involve inflammation. Here, we propose to study the synergistic influences of structural and energetic compromise on BBB function. Building upon our previous findings in iPSC-derived neurons and transformed blood cells, which showed that 22qDS with schizophrenia (SZ) exhibits weaker mitochondrial energetics compared to 22qDS without SZ or non-deleted controls, in Aim 1, we will investigate 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 a more reduced system, outside of the 22qDS context, to study whether OXPHOS compromise will synergize with CLDN5 haploinsufficiency to generate greater BBB insufficiency. We will test whether crossing mice heterozygous only for claudin-5 in the BBB 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 influence of the BBB on neuroinflammation and brain health is increasingly appreciated, this proposal could lead to important novel therapeutics both within and beyond the 22qDS context.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $678,683 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	12/2/2025	NON-COMPETING CONTINUATION	$678,683
														Subtotal = $678,683

Issue Date FY: 2025 ( Subtotal = $673,670 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	11/1/2024	NON-COMPETING CONTINUATION	$572,619
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	2	9/18/2025	NON-COMPETING CONTINUATION	$101,051
														Subtotal = $673,670

Issue Date FY: 2024 ( Subtotal = $612,630 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	1	7/16/2024	NEW	$186,103
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	3/28/2024	NEW	$389,886
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	1	5/1/2024	NEW	$36,641
														Subtotal = $612,630

Grand Total All Awards = $1,964,983

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Mitochondrial influences on blood brain barrier function and neuropsychiatric illness

Award Number: R01MH134893

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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