Amyotrophic lateral sclerosis (ALS), an incurable, progressive, neurodegenerative disease, is characterized by motor neuron death and neuroinflammation. In addition to direct perturbation of motor neurons, mounting evidence suggests that activation of microglia contributes to the pathogenesis of motor neuron dysfunction and death in this disorder. The receptor for advanced glycation end products (RAGE) contributes to neuronal and myeloid, including microglia, dysfunction and promotes sustained inflammatory tissue-damaging responses. Expression of RAGE ligands and RAGE increases in ALS human and murine spinal cord and previous work illustrated that daily administration of soluble extracellular domains of RAGE, or sRAGE, which sequesters ligands and blocks their interaction with the cell surface receptor, to Superoxide dismutase 1 (SOD1)G93A mice, a model of familial ALS (fALS). I hypothesize that RAGE contributes to the perturbation in the ALS spinal cord by promoting neuroinflammation and processes that ultimately lead to irrevocable loss of motor neurons in this disorder. To test this hypothesis, my F31 grant application proposes a single aim; the work of which is in early stages, with supporting preliminary data, at this time. (1) I will intercross Ager-floxed mice (Ager is the gene encoding RAGE) with both SOD1G93A and Tmem119-2A-CreERT2 mice to probe the potential contributions of microglia RAGE to ALS pathology. I have assembled all needed reagents and resources to successfully test this hypothesis. This work will provide a model of proposed RAGE-dependent and cell-type specific perturbations in ALS spinal cord. If successful, my work will unveil novel mechanisms of ?neuro/toxic inflammation? in ALS spinal cord and identify RAGE as a logical therapeutic target in this devastating disorder.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with most patients succumbing to the disease within 3-5 years of diagnosis. ALS is associated with inflammation of glia cells within the central nervous system. In this application, my goal is test the role of a protein linked to inflammation within the central nervous system to identify potential therapeutic targets.
