Harvard Catalyst Profiles

We are investigating molecular genetic mechanisms underlying the development and maintenance of midbrain dopamine neurons and their selective degeneration in Parkinson’s disease (PD) at molecular, cellular, and systemic levels. These studies are leading to the identification of potential drug target(s) to develop mechanism-based neuroprotective therapeutics for neurodegenerative disorders. In this basic/translational research, we identified the orphan nuclear receptor Nurr1 as a potential molecular target for mechanism-based disease-modifying treatment of PD. Although Nurr1 has long been thought to be ligand-independent, we recently identified its synthetic and endogenous ligands and are investigating Nurr1’s functional role in PD pathogenesis and the potential of its ligands for neuroprotective treatment of PD. The student is expected to participate in molecular and cellular studies of PD pathogenesis and Nurr1’s regulation by its ligands. In addition, we are developing stem cell technology to foster a better understanding and treatment of PD and other neurodegenerative disorders. In particular, we are studying molecular mechanisms underlying the reprogramming of cell fate and those underlying the accompanying metabolic changes, so called metabolic reprogramming. We recently identified specific microRNAs that are crucial for metabolic reprogramming and generation of human iPSCs. Based on these mechanisms, we are developing clinical grade safe human iPSC technology and optimizing in vitro differentiation of human iPSCs to functional midbrain dopaminergic cells. These patient iPSC-derived dopamine cells represent an ideal cell source mitigating ethical and medical issues and enable us to perform personalized cell therapy for PD. The student is expected to participate in the further optimization of iPSC technology to make personalized cell therapy a realistic therapeutic approach.