# Probing Role of Tetrahydrobiopterin in Cerebral Palsy by Using Transgenic Rabbits

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $667,532

## Abstract

PROJECT SUMMARY/ABSTRACT
 Children with movement disorders are a big burden to society. The burden of disease is very high because
of the life-long consequences to the patient, caretakers, and social institutions. Currently there are no cures or
preventative treatments for cerebral palsy (CP), as the mechanisms of disease remain poorly defined. Human
mutations in key enzymatic pathways constitute genetic causes of childhood movement disorders. With the
advent of transgenic rabbit models, a golden opportunity has arisen to study the pathogenetic mechanisms in
brain leading to movement disorders, as rabbits are more likely to present with movement disorders mimicking
that of humans. Rabbits are perinatal brain developers like humans. Mutations in enzymes of
tetrahydrobiopterin pathway result in movement disorders. Tetrahydrobiopterin is an enzyme co-factor and its
supplementation in congenital deficiency disorders ameliorates the movement disorder. Thus, there may be a
critical role of tetrahydrobiopterin in the development of movement disorders, such as CP. We developed a
knockout rabbit that introducing a specific mutation in one of the tetrahydrobiopterin synthesis enzymes,
sepiapterin reductase. Following fetal hypoxia-ischemia, newborn rabbits present with hypertonia and difficulty
with balance. Fetal rabbits showing low developmental tetrahydrobiopterin in discrete brain regions have a
greater disposition to develop hypertonia. Magnetic resonance imaging (MRI) allows us to predict which
fetuses will develop postnatal hypertonia. This advance allows the identification of early critical pathways
causing hypertonia. Our objective is to elucidate molecular mechanisms of perinatal brain injury in human
mutations causing childhood movement disorders, by decreasing tetrahydrobiopterin levels using a hetero- and
homozygous knockout transgenic approach in the rabbit. The main question asked in this proposal is whether
tetrahydrobiopterin in selective brain regions contributes to the development of motor disorders with a severity
determined by an added prenatal insult such as hypoxia-ischemia or inflammation. Using genetic knockout of
sepiapterin reductase, we can further lower the tetrahydrobiopterin levels in brain and investigate whether the
resulting motor deficits are increased or that we need less degree of insult to achieve the same motor deficits.
The first Aim determines whether an added fetal insult, hypoxia-ischemia or inflammation from
lipopolysaccharide, enhances movement disorders in the sepiapterin het/homozygous reductase knockout
rabbit. The second Aim will determine if neuronal or oligodendroglial injury explains the development of
movement disorders in the knockout rabbit. We use innovative pre- and postnatal MRI biomarkers of
hypertonia with tissue flow cytometry and high-performance liquid chromatography with electrochemical
detection. By conducting a time-dependent, organ-specific and cell-specific pathogenetic study, we will obta...

## Key facts

- **NIH application ID:** 10148445
- **Project number:** 1R01NS117146-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** SIDHARTHA TAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $667,532
- **Award type:** 1
- **Project period:** 2020-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148445

## Citation

> US National Institutes of Health, RePORTER application 10148445, Probing Role of Tetrahydrobiopterin in Cerebral Palsy by Using Transgenic Rabbits (1R01NS117146-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148445. Licensed CC0.

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