Neuroprotective strategy: novel purine derivatives for neonatal hypoxia-ischemia
Active Project Grant Awarded Last action
- Award ID
- R01NS117428
- Recipient
-
Women & Infants Hospital Of Rhode Island UEI VUYJL5Q7YCZ3
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $5,792,935
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 95% complete
- Originally
- Funding
-
- $5,277,600.00 Federal
- $515,335.00 Non-federal
- Place of performance
- Providence, RI 02905, USA
Award details come from USAspending.gov.
Description
- Abstract
- Hypoxia-ischemia (HI) is the one of leading causes of neurodevelopmental morbidities in preterm and full-term infants. The only therapeutic strategy to treat HI encephalopathy (HIE) in full term infants is hypothermia, which is only partially protective. The only therapy for HI in preterm infants is supportive care. HI brain injury is characterized by a pronounced inflammatory response along with early structural alterations in the blood-brain barrier (BBB)/neurovasculature unit (NVU). Both inflammation and BBB abnormalities predispose to neuronal damage. In the current proposal, we investigate a novel family of molecules, which are purine derivatives (PDD), acting through GSK-3SS and prohibitin (PHB) pathways. PHB protects the integrity of OPA1 in brain mitochondria, which is a particularly important protective protein in the immature brain. Previous studies have shown that OPA1 prevents mitochondrial permeabilization, respiratory deterioration and apoptosis in neurons and vascular beds. Our published data show that PDD i) rescue cognitive deficits associated with aging in mice, II) prevent impairment of neurogenesis, III) enhance synaptic function and IV) reduce neuroinflammatory brain injury in adult mice. GSK-3SS and PHB signaling pathways, including NF-KSS, are involved in the neuroprotective mechanisms of PDD. Our preliminary results in the well-characterized rice-vannucci model of neonatal HI showed that PDD given after HI i) decreased in the HI related infarct volumes by 40%. Our preliminary data suggests pdds exert i) important and consistent neuroprotective effects in neonatal and adult models of brain injury, II) increased OPA-1 expression and III) increased the transcriptional expression of neurotrophic factors in treated female, but not male, neonatal rats after HI. These results suggest induction of neuronal plasticity and OPA-1 expression in this model that could be beneficial after neonatal HI. The overall hypothesis of our proposal is that PDD targets GSK-3SS and PHB to attenuate both the BBB abnormalities and inflammation after neonatal HI. We will test this major hypothesis in two specific aims: aim 1: PDD303 attenuates brain injury in neonatal rats after exposure to moderate and severe HI. Aim 2: treatment with PDD303 improves behavioral outcomes and demonstrates durable long-term neuroprotective efficacy after HI in neonatal subjects. We anticipate that this innovative therapeutic strategy targeting the BBB and neuroinflammation through GSK3SS and PHB could eventually provide an additional treatment strategy to the current standard of care for both full term and premature infants.
Transactions
| Action | Federal | Non-federal | Date |
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| Amendment | $151,138 | $0 | |
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| Amendment | $446,394 | $0 | |
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| Amendment | $446,394 | $0 | |
| Amendment | $515,335 | $0 | |
| Original award | $515,335 | $515,335 |
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Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Commissariat A L' Energie Atomique Et AUX Energies Alternatives | $214,106 | |
| Commissariat A L' Energie Atomique Et AUX Energies Alternatives | $233,115 |
Quick answers
Who received award R01NS117428?
R01NS117428 was awarded to Women & Infants Hospital Of Rhode Island by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on May 1, 2021.
How much is award R01NS117428 worth?
$5,792,935 has been obligated on R01NS117428: $5,277,600 in federal funding and $515,335 in non-federal funding.
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