Role of ASIC1a activation in ECM associated brain injury and mortality - Abstract Cerebral malaria (CM) is a potentially lethal complication of Plasmodium falciparum infections particularly in children <10 yrs of age. Globally, about 500,000 people die of severe malaria of which 30% is attributed to CM. 30% of CM patients fail to survive and 10% of survivors develop neurological complications despite antimalarial therapy. Malaria-induced CNS inflammation, tissue damage and acidosis significantly contribute to CM mortality and posttreatment neurological complications. Thus, effective treatment of CM will require both antimalarial and adjunctive therapy to target these factors. Our long-term goal is to elucidate the molecular basis for the underlying pathogenesis of CM-mediated neurological complications and find adjunctive interventions beyond destruction and elimination of parasites in circulation. Ongoing research for therapeutic agents that block malaria-induced CNS inflammation, tissue damage and acidosis in experimental CM (ECM; P. berghei ANKA in C57BL/6) associated morbidity and mortality identified three promising agents: a Statin (Atorvastatin), a neuropeptide (Neuregulin-1), and an inhibitor of acidosis-mediated activation of acid-sensing ion channel 1a (ASIC1a), which is the focus of this application. ASIC1a is the key proton receptor expressed primarily in neurons of mammalian nervous systems, which mediates acidosis-induced injury of CNS neurons to ischemia. The objective of this application is to investigate the role of ASIC1a activation in the pathogenesis of CM and to establish this channel as a novel target for future therapeutic interventions. The central hypothesis is that ASIC1a activation by acidosis in late-stage ECM contributes significantly to ECM associated brain injury and mortality. A corollary to this hypothesis is that inhibition/deletion of ASIC1a will protect against ECM associated brain injury and mortality. We have generated exciting preliminary data showing that ASIC1a is up-regulated by P. berghei ANKA infection and that inhibitors of ASIC1a extend survival beyond usual timeframe in the absence of antimalarial treatment. With a joint team of investigators with extensive experience in murine ECM model, proteomics, genomics, and neurophysiology, etc., we are well positioned to successfully perform the experiments described in this proposal. Specific Aim 1: Determine the role of ASIC1a gene in ECM pathogenesis. We will test the hypothesis that deletion of the ASIC1a protein will reduce ECM-associated brain injury and mortality or extend survival during ECM pathogenesis. Specific Aim 2: Assess the protective effects of ASIC1a inhibition against ECM-induced brain tissue damage, altered BBB integrity and neurobehavior deficit with or without anti-malarial agent Artemether (ARM). We will test the hypothesis that adjunctive treatment with ASIC1a inhibitors reduces ECM-associated brain injury and mortality.
