Therapeutic Induction of Mitochondrial Biogenesis for the Treatment of Traumatic Brain Injury

Grants and Contracts Details

Description

Traumatic brain injury (TBI) leads to acute necrosis at the site of injury followed by a sequence of secondary events resulting in neuronal cell death. Mitochondria play a pivotal role in mediating these secondary events. Mitochondria are highly dynamic organelles and protecting/restoring mitochondrial function improves neuronal function after TBI. Here, we propose to use a novel approach of activating mitochondrial biogenesis (MB) after TBI using pharmacological intervention. MB is a necessary cellular process to replace dysfunctional mitochondria that involves a complicated signaling network involving peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1á) as a master regulator. Activation of MB can be an important intervention to modulate mitochondrial dynamics and protect/restore mitochondrial function after TBI. We propose that Formoterol, a highly selective â2-adrenergic receptor agonist may induce MB and protect/restore neuronal function during secondary damage from controlled cortical impact (CCI) in 7-9 week old C57BL/6 male mice. To achieve this, in specific aim 1 we will examine the temporal aspects of MB and pharmacological intervention of Formoterol-induced MB activation in mouse brain by analyzing molecular markers of MB. In specific aim 2 we will establish the effective therapeutic window of intervention for Formoterol treatment to improve mitochondrial function after TBI in mice using mitochondrial bioenergetics as an endpoint. In specific aim 3 we will determine the pre-clinical efficacy of the optimal Formoterol dosage for long-term neuroprotection following TBI in mice. We hypothesize that optimizing the therapeutic window and dose response of Formoterol treatment after TBI by analyzing the molecular markers of MB along with mitochondrial bioenergetics would lead to improved functional outcome in terms of memory and learning outcome after TBI.
StatusActive
Effective start/end date5/15/215/14/25

Funding

  • KY Spinal Cord and Head Injury Research Trust: $300,000.00

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