Despite significant advances in our understanding of the consequences of neuronal stress at molecular levels, interventions for neuronal injury, as in stroke, remain elusive. One approach is to identify changes in neuronal metabolism incurred as a consequence of oxidative or metabolic stress that may be neuroprotective, or, alternatively, that may be pro-apoptotic. AMP-activated protein kinase (AMPK) is a known sensor of peripheral energy balance, and is activated when energy sources are low. Peripherally, AMPK acutely regulates cellular metabolism and chronically regulates gene expression. We demonstrated that AMPK in highly expressed in neurons and responds to metabolic challenges by altering neuronal metabolism, suggesting that AMPK may play a physiological role in regulating neuronal energy balance. However, AMPK activation appears to be deleterious in stroke models, in a parallel line of investigation, we have established roles for the fatty acid synthase (FAS) pathway and carnitine palmitoyltransferase (CPT-1) in metabolism and as targets for modulating cellular energy utilization/perception. We have shown that modulation of these pathways by synthetic FAS inhibitors/CPT-1 stimulators that we designed, such as C75, can alter neuronal metabolism. Most recently, we have combined these lines of investigation and shown that C75 inhibits AMPK activation in vitro and in vivo and significantly reduces stroke volume. Our hypothesis is that AMPK plays a role in neuronal energy perception, but its over-activation with metabolic failure is deleterious; furthermore, modulation of the FAS/CPT-1 pathway alters neuronal metabolism to inhibit AMPK and produce neuroprotection under conditions of cellular stress.
Aim 1 will use in vitro models to define the regulation of AMPK activity in neurons.
Aim 2 will study the role and regulation of AMPK in an ischemia-reperfusion model.
Aim 3 will determine the mechanisms by which modulation of the FAS and CPT-1 activities alters AMPK activity and affords neuroprotection.
| Ronnett, Gabriele V; Ramamurthy, Santosh; Kleman, Amy M et al. (2009) AMPK in the brain: its roles in energy balance and neuroprotection. J Neurochem 109 Suppl 1:17-23 |
| Kleman, Amy M; Yuan, Jason Y; Aja, Susan et al. (2008) Physiological glucose is critical for optimized neuronal viability and AMPK responsiveness in vitro. J Neurosci Methods 167:292-301 |
| Kim, Eun-Kyoung; Kleman, Amy M; Ronnett, Gabriele V (2007) Fatty acid synthase gene regulation in primary hypothalamic neurons. Neurosci Lett 423:200-4 |
