Research

Our lab is interested in understanding how neurotrophic growth factors, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), regulate nervous system function and modulate neuropsychiatric and neurodegenerative disease. We study neurotrophin actions through the identification of gene products that these growth factors regulate in the CNS and PNS, determining how these proteins are involved in neurogenesis, axonal outgrowth and pathfinding, synaptogenesis, and synaptic plasticity, using cellular and molecular tools, and knockout mouse models. Previous studies identified the NGF-regulated cell surface adhesion protein, called NILEGP or L1, an immunoglobulin (Ig) superfamily member that is expressed primarily in the nervous system, and investigated how this cell adhesion molecule regulated axonal outgrowth, branching, pathfinding, and fasciculation. In recent work we’re investigating how the neurotrophin-inducible gene Vgf, encoding a secreted ‘granin-like’ protein and peptide precursor, controls energy expenditure, memory, and depression-like behavior, impacting neuropsychiatric and neurodegenerative disorders such as Major Depressive Disorder (MDD) and Alzheimer’s disease (AD). VGF-derived peptides injected into the brain were found to have anti-depressant efficacy, and to reduce cognitive decline and neurodegeneration in mouse models of AD, consistent with abnormalities noted in memory tasks and depressed behavior in our VGF knockout mice. We are developing novel conditional and humanized knockout models and are utilizing Adeno-Associated Virus (AAV) gene therapy approaches to better understand the function in the nervous system of VGF, VGF-derived neuropeptides and their novel receptors, and key hub proteins in the VGF multiscale causal network. In recent preclinical studies we have also been evaluating the efficacy of chronic intranasal ‘nose-to-brain’ VGF peptide delivery to reverse Alzheimer’s disease-like phenotypes in mouse amyloidopathy and tauopathy models.