R01NS117146

Probing Role of Tetrahydrobiopterin in Cerebral Palsy by Using Transgenic Rabbits - 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 the 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 the 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 introduces 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 the brain and investigate whether the resulting motor deficits are increased or if we need a lesser 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 hetero- and 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 obtain a comprehensive picture of the role of this cofactor in perinatal pathogenesis of movement disorders.

Wayne State University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Detroit, Michigan 48202 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 367% from $667,532 to $3,115,975.