Area of Interest: Human stem cells; Cocaine addiction; Schizophrenia; Synaptogenesis; Estrogen hormones and synaptic plasticity. Project 1: Study the molecular mechanism of cocaine addiction using human induced pluripotent stem cells (iPSCs) (funded by National Institute of Drug Abuse/NIH). Cocaine abuse remains a major public health problem. The long-lasting nature of addiction leads to relapse and makes it especially difficult to treat. Despite decades of research, no effective treatment is available for cocaine addiction. A better understanding of the development of addiction is essential for creating effective therapy for cocaine addiction. Our knowledge about cocaine addiction has been generated mostly from studies with animal models, with limited contributions from information about human neuronal pathology obtained by analyzing PET (Positron emission tomography) images and postmortem brain tissues of end-stage cocaine addicts. However, the cellular/molecular mechanisms of human cocaine addiction are little known because it has been difficult to obtain differentiated neurons from cocaine addicts for molecular analysis. Patient-derived iPSCs provide an excellent platform for exploring the mechanisms of cocaine addiction. The aims of this project are to investigate the molecular mechanism of cocaine addiction using human iPSCs. This study will help to understand the molecular mechanisms of cocaine addiction, and generate important tools/foundation for cocaine addiction research. In addition, another project of the lab is to understand the molecular mechanisms of cocaine addiction using animal models including rats and transgenetic mice. Project 2: Study the role of Kalirin in human embryonic stem cells (hESCs) and iPSC-derived neurons from schizophrenia (funded by Connecticut Stem Cell Program). Schizophrenia (SZ) is a serious mental health disorder with a lifetime prevalence of about 1%. Patients experience very severe symptoms with an increased risk for suicide, unemployment, permanent disability and homelessness. The causes of schizophrenia are currently unknown, but synaptic and dendrite pathology is altered in SZ, with selective impairments of synaptic machinery within cerebral cortical circuits. Dendritic spine density on pyramidal neurons is decreased, and about 60% of the excitatory synapses in the prefrontal cortex are lost in some SZ patients. Modulating synaptic plasticity might be a promising therapeutic approach to SZ. Kalirin is identified as a risk factor for schizophrenia and is one of several genes known to be required for synapse formation in hippocampal/cortical neurons in rodent. Kalirin expression which was decreased in the cortex of SZ patients is strongly correlated with spine density in SZ subjects. Reduced Kalirin expression might reduce spine density in SZ, impairing formation of new spines and decreasing stability of mature spines. Mice that do not have the Kalirin gene have fewer spines/synapses and exhibit some schizophrenia-like phenotypes. Patient-derived iPSCs are an excellent platform for exploring disease mechanisms. The aims of this project are to study the functions of Kalirin in hESC-derived and iPSC-derived neurons; these iPSC-derived neurons will be generated from schizophrenic patients and healthy controls. Results from this study will pave a path for developing new therapeutic approaches for the treatment of this human disease. These projects are a collaboration with Dr. Xue-Jun Li at UCHC Neuroscience. Project 3: Study the molecular mechanisms through which estrogen regulates synaptic plasticity in hippocampal neurons (funded by National Institute of Mental Health/NIH). The focus is to study how estrogen alters Kalilrin7 expression and other synaptic proteins that play an important role in regulating spine formation and synaptogenesis in hippocampal neurons. Kalirin7, a major isoform of Kalirin, is localized to the postsynaptic side of excitatory synapses. Kalirin7 causes an increase in spine density when over-expressed and the number of dendritic spines decreases when the levels of endogenous Kalirin7 are reduced in hippocampal neurons. Kalirin7 plays a key role in estrogen-mediated spine/synapse formation in hippocampal neurons. Kalirin7 is also an essential determinant of dendritic spine formation following chronic cocaine treatment. Hippocampal CA1 pyramidal neurons of Kalirin7 knockout (Kalirin7KO) mice show decreased spine density, spine length, synapse number and postsynaptic density size in their apical dendrites, are deficient in long-term potentiation, and exhibit decreased frequency of spontaneous excitatory postsynaptic current. Behaviorally, Kalirin7KO mice show decreased anxiety-like behavior and impaired acquisition of a passive avoidance task. Experimental techniques required for these projects include cell cultures, primary hippocampal neuron cultures, construct DNA vectors, real-time PCR, Western blot analysis, immunohistochemistry, generation of human induced pluripotent stem cells, neural differentiation of stem cells, confocal microscope, electrophysiology and image analysis.

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