Topic: Acid Sensing Ion Channels (ASICs) as a therapeutic target in amyotrophic lateral sclerosis
Contact: Prof Jochen Prehn, Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin 2, Ireland
Email: prehn@rcsi.ie
Description:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. Metabolic stress is believed to occur in the spinal cord and motor cortex of ALS patients as a result of mitochondrial dysfunction, excessive Ca2+ overloading, and/or in response to a local hypoxic/ischemic environment. Because of emerging preliminary findings from our group that demonstrated metabolic alterations favouring acidotoxicity in ALS, we aim to investigate the role of acid sensing ion channels (ASICs) as a new therapeutic target for the treatment of ALS.
ASICs are a group of amiloride-sensitive ion channels activated by protons which may cause neuronal cell death through toxic Ca2+ and Na+ influx (Xiong et al., 2004). The overall aim of this research is to provide experiemental proof for a role of ASIC1a and ASIC2 channels in the pathophysiology and to provide a rationale for the use of ASIC inhibitors to therapeutically treat ALS. In this project, you would be responsible for investigating the effect of specific ASIC inhibitors on life span and disease progression in two distinct in vivo models of ALS, the SODG93A and TDP43A315T mouse models (Kieran D, et al., 2008; Sebastia et al., 2009). You would be comprehensively exploring the involvement of ASIC channels in the neuroprotective action of ASIC inhibitors in motoneurons in vitro as well as in post-mortem patient tissue.
Given the preliminary work we have undertaken for this project and the technical experience incumbent in our laboratory, we anticipate this project to be suitable for a qualified neurobiologist with experience in molecular biology and/or working with in vivo models of disease. Excellent organizational skills and a genuine interest in neuroscience are essential. A background in ALS research or neurodegeneration research would be preferred.
References:
Kieran D, et al. (2008) Control of motoneuron survival by angiogenin. J Neurosci 28(52):14056-14061.
Sebastia J, et al. (2009) Angiogenin protects motoneurons against hypoxic injury. Cell Death Differ 16(9):1238-1247.
Xiong ZG, et al. (2004) Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118(6):687-698.