Discovering Novel Drug Targets for CNS Edema by In Vitro Genetics

AbstractBrain swelling is a serious complication of traumatic brain injuryTBIischemic stroke and other serious conditionsTBI and stroke afflictM andK persons per year in the US aloneThey are a costly health care burden and a devastating social burdenCurrent treatments for brain swelling are limited and generally ineffectivehighlighting the dramatic unmet need for better therapeuticsA better understanding of the molecular pathways and cellular mechanisms is sorely needed to identify new drug targets and predictive biomarkers that can stratify patients for clinical treatment decisionsThe goal of this project is to identify new drug targets and biomarkers of response for cytotoxic edema of astrocytesWe will use a novel and innovative technology that we have developed that takes an unbiased approach to functionally identifying the causal mediators of brain cell swellingOur approach uses a large panel of genetically diverse astrocyte lines to identify the genes and pathways that mechanistically underlie cytotoxic edemaIn Phase Iwe developed a high throughput kinetic assay for astrocyte swelling that is robust and scalable for screening compounds that induce or block swellingIn Phase II we will screengenetically diverse astrocyte cell lines and then map and identify the genes that mediate response to inducers and blockers of cell swellingValidation of candidate target genes will be conducted in both human and mouse astrocytesHuman genes that modify human astrocyte response that are also therapeutically accessible target genes for novel drug discovery are the ultimate aims and products of this project Brain swellingcerebral edemais a serious consequence of many disorders such as traumatic brain injury and strokeA more complete understanding of the molecular pathways underlying cerebral edema is a critical bottleneck in the development of new drugs for brain swellingWe want to understand the molecular mechanisms underlying swelling in astrocytesthe most abundant cell type in the braintoward the discovery of more effective treatments for brain edema!