Johns Hopkins School of Medicine

Molecular Neurobiology of Neurodegeneration, and Glial Biology

Professor, Department of Neurology and Neuroscience and Director for the Brain Science institute a neurologist/neurobiologist with a major commitment to investigations of the biology underlying neurodegenerative disease, with a specific focus on amyotrophic lateral sclerosis. His research focuses, of several pathways of cellular dysfunction including a major focus on the biology of the nuclear pore, nucleoporins and nuclear transport in ALS, Huntingtons disease and dementias. He has a long studied the biology of astroglia, and their fundamental regulatory functions in the CNS including glutamate transporters and lactate transporters and their role in acute and chronic neurodegeneration. Recent work has focused on astrocyte subtypes, such as layer specific astroglia, their local regulatory function in neuronal synapse and synapse formation. Recent work has also included the role of oligodendroglia and their precursors in contributing to early neurodegeneration, their functions in metabolically supporting axon. The lab is especially focused on regulation of nuclear transport, MCT1 lactate transport and glutamate transport by drugs acting to activate transporter transcription, nuclear and cytoplasmic and membrane interacting proteins which regulate the processing of transporter subtypes. The group has cloned and characterized multiple transporters for glutamate, regulatory protein for glutamate transporters and nuclear transport.

Much of the work employs a large library of human induced pluripotent stem cell (iPSC) used to endogenously study human disease (ALS, FTD) and his lab runs Answer ALS consortium a national program to generate >1000 ALS and control iPS cell lines- differentiated into neurons: cortical and spinal, astroglia and oligodendroglia, which then undergo extensive multi-omics analytics- whole genome, epigenome, RNA profiling and proteome.

Members of the lab focus on the role of nuclear pore proteins (nucleoporins), transporter interacting proteins to modulate membrane trafficking, assembly and cellular processing of transporters. As a component of many of these studies the lab has generated BAC transgenic mice expressing promoter reporters for each of the glutamate and lactate transporters- GLT1, EAAT4 and GLAST. The also study the deregulation of glutamate transporter synthesis and metabolism in ALS.

Other projects in the laboratory focus on the biology of glutamate transport function and regulation: identification of neuronal factors and growth factors that regulate the normal expression of transporter subtypes, the role of EAAC1 in epilepsy, trafficking and pathobiology of truncated astroglial glutamate transporters, interacting proteins for the astroglial glutamate transporters. His lab uses high and low thruput systems and chemical libraries to identify drugs that activate EAAT genes for therapeutics. Studies on transgenic models of ALS include: neuroprotective studies using viral vector delivery approaches, neuroprotectant discovery, glial progenitor as neuroprotectants and neural and astroglial stem cell therapies in ALS -relevant models.