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 inhibition of several neuroprotective pathways. Our preliminary data show that early down-regulation of survival pathways including Akt occur in the cortex after TBI and may play a significant role in shifting the survival/apoptosi balance toward neuronal cell death. Furthermore, we show that rapid elevation in select microRNAs such as miR-711 may be an important regulator of these pathophysiologic events. We propose to use various molecular techniques in in vitro and in vivo neuronal injury models including central and systemic administration of miR inhibitors to test our central hypothesis that inhibition of multiple neuroprotective mechanisms in response to miR-711 up-regulation leads to unconstrained activation of pro-apoptotic pathways and represents a key mechanism of neuronal loss and neurological deficits after TBI.
Specific Aims :
Aim 1. To determine the miR-711 regulation and mechanistic effects in neuronal cell death. STUDY #1.1 Demonstrate that rapid elevation of miR-711 is a key cell death pathway in multiple models of neuronal apoptosis. STUDY #1.2 Characterize the miR-711 promoter activity in neuronal apoptosis. STUDY #1.3 Characterize the targets of miR-711 in neuronal apoptosis.
Aim 2. To examine the miR-711 regulation and mechanisms of miR-711-dependent neuronal cell death after experimental TBI. Study #2.1 Demonstrate that rapid elevation of miR-711 leads to neuronal cell death after TBI. Study #2.2 Identify key molecular targets of miR-711 and its impact on apoptotic pathways after TBI. Study #2.3 Identify miR-711 transcriptional modulators after TBI.
Aim 3. To examine the neuroprotective effects of miR-711 inhibitors following central and/or systemic administration as well as to determine their therapeutic window after CCI. Study #3.1 Determine the therapeutic window of central (icv) administration of miR-711 inhibitors on neuronal loss and functional deficits after brain trauma. Study #3.2 Examine the therapeutic effects of systemic administration of miR inhibitors on neuronal loss and functional deficits after brain trauma.
Traumatic brain injury (TBI) impacts millions of individuals world-wide each year, resulting in significant mortality as well as chronic disabilities. TBI is associated with significant neuronal cell death, which is caused by multiple, often inter-connected pathways. Here we propose to examine rapid miR-711 upregulation as a key mechanism of neuronal apoptosis after TBI. We will explore the potential role of miR-711 as an important negative regulator that blocks multiple neuroprotective/survival pathways shifting the balance in favor of neuronal cell death. Thus, miR-711 inhibitors 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 |
