My research focus has been the study of molecular genetic mechanisms underlying the development and maintenance of midbrain dopamine neurons in health and disease. These studies are leading to the identification of potential drug target(s) to develop mechanism-based neuroprotective therapeutics for neurodegenerative disorders. In addition, my laboratory is developing stem cell technology to foster a better understanding and treatment of neurodegenerative disorders.
Firstly, we identified and characterized several fate-determining transcription factors playing key roles in the development and survival of midbrain dopamine neurons, leading to implementing translational research with potential preclinical and clinical applications. In particular, we focused our attention on the orphan nuclear receptor Nurr1 as a potential drug target. Nurr1 is critical not only for the development and long-term maintenance of midbrain dopamine neurons, but also for their protection from inflammation-induced cell death by suppressing pro-inflammatory gene expression. Furthermore, Nurr1 is emerging as a promising target for other neurodegenerative disorders as well as autoimmune disorders. To accomplish our goal we established efficient high throughput screening assays and identified both synthetic and native agonists that can boost Nurr1's transcriptional activity.
Secondly, we have keen interest in understanding the molecular mechanisms underlying the reprogramming of cell fate and those underlying the accompanying metabolic changes, so called metabolic reprogramming. We recently found that SIRT1 upregulation and SIRT2 downregulation is a molecular signature of human pluripotency and that the miR200c-SIRT2 axis is critical for metabolic reprogramming. Based on these mechanisms, we are developing clinical grade safe induced pluripotent stem (iPS) cell technology and optimizing their in vitro differentiation to functional midbrain dopaminergic cells. These iPS-derived dopamine cells represent an ideal cell source mitigating ethical and medical issues. Thus, we are currently developing safe and efficient stem cell technology towards the establishment of personalized cell therapy for Parkinson's disease and other degenerative diseases.
Molecular Neurobiology Lab, Room 216
115 Mill Street
Belmont, MA 02478