B.S., Nankai University, 1996
M.S. University of Medicine and Dentistry of New Jersey, 2002
Ph.D., University of Michigan, 2005
Harvard Medical School
Massachusetts Institute of Technology
Scientist Development Award, AHA, 2013
Young Investigator Award, NARSAD, 2013
Katowitz/Radin Investigator Award, NARSAD, 2008
Young Investigator Award, NARSAD, 2007
The sophisticated human behaviors, such as language, tool use, and self awareness, require an extraordinary diversity of the neuronal population in the human brain. Such complexity results from neural stem/progenitor cells (NPCs) in the embryo with the ability to generate every cell type in the brain. The fundamental question in neurobiology is how NPCs self renew and give rise to enormously diverse neuronal cell types, which interconnect with amazing specificity to form functional neural circuits. Until recently, the functional relevance of disturbed neurogenesis to the pathophysiology of psychiatric disorders has just emerged. Schizophrenia is a severe psychiatric illness that affects 0.5-1 percent of the world population. Wile the etiology is poorly understood, emerging evidence hints that certain abnormal modifications in neurodevelopment may contribute to the etiology of psychiatric disorders.
The ultimate goal of our lab is to help develop better therapies and cures for mental illnesses. To achieve this, our lab focuses on understanding the mechanisms that lead to abnormal behaviors. In particular, we utilize cross-disciplinary techniques to overcome challenges that others have not been able to address. The research of our lab focuses on the mechanisms that regulate neurogenesis using mouse models and human stem cells. In the short term, we would like to focus our research program on determining how abnormal NPC proliferation and differentiation may lead to mental illnesses. Our long-term plan is to use the reagents, experimental systems, and mouse models that we develop to further screen novel drugs that can reverse the behavior phenotype in our mouse model and eventually benefit patients with psychiatric disorders.
Neural Progenitor Subtypes During Neurodevelopment
The cerebral cortex is the most complex brain structure within distinct subtypes of projection neurons located in six highly organized layers. We study the relationships among different NPCs and projection neuron subtypes and the genes that determine progenitor subtypes.
Genetic Mouse Models and iPS Model for Psychiatric Disorders
The neurodevelopmental hypothesis provides a promising approach to explore the pathogenesis of psychiatric disorders. By uncovering a new role for the schizophrenia candidate gene DISC1 in embryonic and adult neural progenitor proliferation, we connected NPC proliferation with schizophrenia (Cell 136: 1017). Our data suggest that decreased neural progenitor proliferation and defective differentiation may lead to psychiatric disorders.
Wnt Signaling Defect in Psychiatric Disorders
In parallel, we investigate whether other Wnt regulators modulate the neural stem cell proliferation and are involve in regulating mouse behavior. In the initial RNAi screen using a Wnt reporter assay, we identified multiple genes that modulate the strength of Wnt signaling, and some of them have been shown to be deleted in a genome-wide survey of rare copy number variants (CNVs) associated with schizophrenia. Thus, mouse models with different defects in Wnt signaling might be of great interest in relation to psychotic disorders. Using biochemical and cellular techniques, we will further investigate how these genes are involved in regulating Wnt signaling.
Development of Specific Inhibitor for Psychiatric Diseases
It is striking that many of the risk genes associated with schizophrenia directly or indirectly affect GSK3 regulatory pathways. Likewise, many drugs that modulate psychosis, including lithium and clozapine, alter GSK3 signaling. Some GSK3 inhibitors have been used for maintenance of embryonic stem cell self-renewal. Our results suggest that defects in neural stem cell proliferation may cause abnormal behaviors, which provides important insight into the pathophysiology of psychiatric disorders and offers potential avenues for therapeutic intervention. Our long-term goal is to develop specific GSK3 inhibitors that may maintain neural stem cell proliferation during psychiatric diseases, but do not interrupt other normal GSK3 functions. These inhibitors can be further validated using the patient-specific iPS cells and mouse models established in our lab.