Professor
Center for Neurologic Diseases
The human brain remains one of life’s greatest mysteries and challenges, being responsible for all human activities that require its myriad functions. However, our understanding of the brain remains incomplete and this deficiency is perhaps most evident through hundreds of brain diseases that lack genuine disease-modifying therapies, let alone cures. My laboratory continues to contribute to our understanding of the brain, while also pursuing novel therapeutic avenues.
During the last quarter century, it has become clear that brain cells — particularly post-mitotic neurons — have distinct genomes that vary at the level of their DNA sequencing, arising somatically, without affecting the germline, to produce somatic genomic mosaicism.
Many forms have been identified, from aneuploidies to copy number variations (CNVs) to repeat elements like LINE-1 to single nucleotide variations (SNVs); mostly affecting non-coding sequences.
However, more recently, reverse transcriptase (RT)-mediated somatic gene recombination (RT-SGR) identified within neurons to produce “genomic cDNAs” or “gencDNAs” was found to affect cellular genes to produce new genes, CNVs, structural variants and mutations. In Alzheimer’s disease and likely other neurodegenerative conditions, new gencDNAs and endogenous active RT offer potential drug targets for intervention, which we are exploring, along with identifying new genes affected by RT-SGR.
We are also studying lysophospholipid receptors, a class of G protein-coupled receptors that we have found to be involved in many biological process and amenable to therapeutics, particularly the treatment of multiple sclerosis (MS) where work has contributed to the entry of five FDA-approved drugs to treat MS and other disorders.
Ongoing studies continue to uncover molecular pathways involving these receptors towards finding new treatments for additional neurological as well as non-neurological disorders.