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Aldo-keto reductase’s mechanism in brain injury from hypoxia-ischemia and tetrahydrobiopterin deficiency

Award Number: R01NS146896
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Aldo-keto reductase’s mechanism in brain injury from hypoxia-ischemia and tetrahydrobiopterin deficiency - PROJECT SUMMARY/ABSTRACT Congenital tetrahydrobiopterin (BH4) deficiency causes motor and behavioral impairments and irreversible intellectual disabilities. Currently, no definitive therapies exist to effectively restore BH4 levels in the human brain, and clinical management is largely limited to correcting dopamine and serotonin deficiencies. Hyperphenylalaninemia (HPA) is a common manifestation of BH4 deficits, except in cases resulting from pathogenic variants in sepiapterin reductase (SPR), a key enzyme in BH4 synthesis. This exception is believed to reflect compensatory activity of aldo-keto reductase (AKR) enzymes, which are abundant in the liver and can substitute for SPR to sustain BH4 production. However, the role of AKRs in the brain remains poorly understood. If AKR activity in the brain can be harnessed, it may offer a novel neuroprotective strategy to boost BH4 levels. Notably, AKR expression is regulated by the transcription factor Nrf2. The primary goal of this proposal is to evaluate the therapeutic potential of AKRs and elucidate the mechanisms regulating BH4 synthesis in the brain. We hypothesize that specific AKRs can mitigate BH4 and neurotransmitter deficiencies, thereby improving neuronal and motor function. Our prior work demonstrates that antenatal hypoxia–ischemia (H-I) causes BH4 depletion and hypertonia. To further investigate the link between BH4 loss and motor dysfunction, we have generated transgenic SPR-knockout (SPR-KO) rabbits, a powerful toolkit for developmental neuroscience. These animals display motor deficits at birth, providing distinct advantages over mouse models, including spontaneous motor impairments and the absence of HPA. This study will be the first to define the role of AKRs in a preclinical rabbit model. To establish the relevance of AKR in improving cell function, we aim to 1) determine whether AKR induction enhances BH4 synthesis in neuronal cells to levels meeting or exceeding the physiological threshold, using AKR knock-in and CRISPR/Cas9-engineered SPR-KO cell lines lacking alternative reductases. Additionally, we will 2) investigate whether pharmacological AKR activation stabilizes tyrosine hydroxylase and improves dopamine production in neuronal cells from distinct brain regions of SPR-KO rabbits, identifying optimal dosing and timing to inform in vivo studies. Importantly, we will assess whether AKR- mediated BH4 synthesis triggers region-specific responses in the brain, ultimately ameliorating motor function. Finally, we will examine wild-type and SPR-KO fetal rabbits and inducers of AKR to 3) determine whether AKR- mediated BH4 synthesis reduces H-I–induced hypertonia and define the underlying mechanisms by comparing hypertonic and non-hypertonic animals. By integrating molecular, cellular, and behavioral approaches, this project seeks to establish AKRs as a novel therapeutic target for BH4-related neurological disorders and lay the groundwork for innovative strategies to enhance neuroprotection and motor function.


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 = $625,792 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/9/2026	NEW	$625,792
														Subtotal = $625,792

Grand Total All Awards = $625,792

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Aldo-keto reductase’s mechanism in brain injury from hypoxia-ischemia and tetrahydrobiopterin deficiency

Award Number: R01NS146896

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/09/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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