SBIR-STTR Award

Aberrant apoptosis is implicated in several neurodegenerative disorders including, stroke, brain trauma, spinal cord injury, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's and Huntington's disease. These neurodegenerative diseases are associated with high morbidity and mortality, and treatment options are limited. Agents that modulate apoptosis are a major focus of drug development efforts by biopharmaceutical companies. Assessment of drug effects in a convenient vertebrate model, prior to proceeding to evaluation in complex systems, such as mouse, can potentially streamline drug development and dramatically reduce costs. Zebrafish mutants exhibiting aberrant apoptosis in the central nervous system are an excellent animal model for studying neurodegeneration. Using a zebrafish neurodegenerative mutant line and a vital dye apoptosis assay, this Small Business Innovation Research project proposes to characterize embryogenesis and apoptotic patterning in zebrafish embryos, and to develop a rapid and effective in vivo screen for neuroprotective therapeutics

Neuronal apoptosis has been shown to be involved in pathogenesis of several neurodegenerative disorders including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotophic Lateral Sclerosis (ALS) and stroke. Currently, there is no simple method to assess neuronal apoptosis or neuroprotection in vivo in vertebrates. Furthermore, conventional vertebrate assays, which are lengthy and laborious, are impractical for screening compound libraries. A validated in vivo assay will be useful for prescreening drug candidates prior to performing expensive mammalian testing. The overall aim of this research is to develop a rapid, quantitative in vivo zebrafish assay to identify potential neuroprotectants. Phase I research established a reproducible model for generating apoptosis in the brain and developed methods for screening neuroprotectants in vivo. Phase II research will automate the assay to increase screening throughput, perform a pilot screen using a compound library and confirm neuroprotective effects of "hit" compounds using a conventional mammalian model. By providing a rapid in vivo assay for prescreening drug candidates prior to performing expensive mammalian testing, the proposed zebrafish assay will facilitate drug development for neurodegenerative disorders and stroke