Traumatic brain injury (TBI) leads to neuronal cell loss and associated motor and cognitive deficits. The underlying neuronal cell death is mediated through multiple interconnected mechanisms, which include activation of multiple BH3-only and multi BH-domain pro-apoptotic proteins. Our preliminary data show that early up-regulation of these pro-apoptotic Bcl2 family proteins occur in the cortex after TBI and may play a significant role in neuronal cell death. Furthermore, we show that changes in specific microRNAs such as miR- 23a and -27a may be an important regulator of these pathophysiologic events. We propose to use genetically engineered mouse models and central administration of miR mimics to test our central hypothesis that combined modulation of multiple pro-apoptotic BH3-only as well as multi BH-domain molecules via miR- 23a/27a mimics results in superior attenuation of neuronal damage and improved reduction in neurological deficits after TBI, compared to more targeted interventions directed toward individual BH3-only pathways.
Specific Aims will show that:
Aim 1. To determine the individual and additive neuroprotection provided by inhibiting specific pro-apoptotic Bcl2 molecules after TBI. Study #1.1 Demonstrate the effects of constitutive deletion of Puma, Noxa or Bim on neuronal loss and functional deficits after brain trauma. Study #1.2 Compare the additive neuroprotective effects of Puma-/-/Noxa-/-/Bim-/- triple KO with those of Bax-/- Bak-/- double KO on neuronal loss and functional deficits after brain trauma Aim 2. To examine the mechanisms underpinning the rapid down-regulation of miR23a/27a and identify their key targets in neuronal apoptosis in vitro. Study #2 Identify the regulators of transcription and key targets for miR23a/27a in various models of neuronal apoptosis Aim 3. To demonstrate the relative neuroprotective effects of miR-23a and -27a as well as their additive benefits and therapeutic window; examine their modulation and targets after TBI in vivo. Study #3.1 Examine effects of acute central (icv) administration of miR-23a and/or miR-27a mimics on neuronal loss and functional deficits after brain trauma Study #3.2 Examine the therapeutic window of delayed central (icv) administration of miR mimics on neuronal loss and functional deficits after brain trauma after TBI with an extended therapeutic window.
Traumatic brain injury (TBI) impacts millions of individuals world-wide each year, resulting in significant mortality as well as chronic disabilities, and TBI i associated with significant neuronal cell death, which is caused by multiple, often inter-connected mechanisms. Here we propose to examine pro-apoptotic Bcl2 molecules as key mechanisms of neuronal programmed cell death after TBI and to explore the potential role of miR-23a and -27a as important regulators that block multiple apoptotic pathways. Thus, miR-23a/27a are expected to robustly attenuate TBI induced neuronal loss and reduce post-traumatic neurological deficits and may lay the foundation for novel therapeutic strategies.
| Aubrecht, Taryn G; Faden, Alan I; Sabirzhanov, Boris et al. (2018) Comparing effects of CDK inhibition and E2F1/2 ablation on neuronal cell death pathways in vitro and after traumatic brain injury. Cell Death Dis 9:1121 |
| Sabirzhanov, Boris; Faden, Alan I; Aubrecht, Taryn et al. (2018) MicroRNA-711-Induced Downregulation of Angiopoietin-1 Mediates Neuronal Cell Death. J Neurotrauma 35:2462-2481 |
