Current Research and Scholarly Interests
Clinical interests include Alzheimer’s disease and Huntington’s disease and the development of effective therapeutics for these disorders.
Our research group is focused on the discovery of cellular signaling mechanisms that serve as a basis for the development of novel therapeutic approaches for Alzheimer’s disease, Huntington’s disease and other neurological disorders. In our Neurotrophin Program, we have pioneered the development of small molecule ligands targeted to neurotrophin receptors to promote novel signaling mechanisms. Small molecule-induced activation of these mechanisms demonstrates therapeutic efficacy in models of Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, Parkinson’s disease, Rett syndrome, spinal cord injury, HIV dementia, peripheral neuropathy and other areas. These novel compounds also promote neurogenesis from stem cells. As part of a traditionally very rare scenario in academic neurology and neuroscience, one of our novel small molecules has moved through phase one clinical trials and is currently in a phase 2a trial in Alzheimer’s patients.
In our Protein Tyrosine Phosphatase (PTP) Receptor Program we have been among the leaders in elucidating the role of PTP receptors in the nervous system. We have focused on LAR, a prototype PTP receptor that we discovered to be expressed in the nervous system. Our studies demonstrated the first CNS and PNS phenotypes in a PTP receptor mutant mouse, discovered PTP extracellular domains responsible for their potent neurite promoting effects, found that LAR associates with Trk neurotrophin receptors to regulate their activity, showed that down regulating LAR promotes stem cell proliferation and stimulates hippocampal neurogenesis, and developed a novel approach for down regulating PTP activity. Our team pioneered the first synthetic peptides, with one set modeled on a LAR intracellular domain and other on an extracellular domain, capable of modulating LAR activity. These peptides have provided a novel approach for modulating PTP receptors and have made possible translational research studies by ours and other laboratories in the areas of novel therapies for spinal cord injury and brain tumors. This work also reveals candidate therapeutic targets for small molecule development.