I. MECHANISMS OF CORTICAL NEUROGENESIS
One of our research interests is to elucidate signal transduction mechanisms that regulate cortical neurogenesis, i.e. what makes a neural stem cell proliferate and differentiate into neurons during cortical development. Specifically, recent studies in our lab suggest a novel role for the extracellular-signal-regulated kinase 5 (ERK5) MAP kinase in regulating the fate choice of cortical stem cells. The elucidation of molecular mechanisms that regulate neural progenitor cell proliferation and differentiation into neurons is important for an understanding of neural developmental and neurodegenerative diseases. Furthermore, stem cell-based cell replacement therapy offers enormous potential for the treatment of a variety of developmental, psychiatric, neurodegenerative and aging related diseases for which there are currently no cures. Moreover, environmental toxicants may cause developmental neurotoxicity by perturbing these signaling mechanisms that regulate neurogenesis.
II. MECHANISMS FOR REGULATION OF NEURONAL APOPTOSIS
Our laboratory is also interested in molecular mechanisms and signal transduction pathways that control neuronal survival and cell death. Abnormal apoptosis may cause or contribute to various neurodegenerative disorders including Huntington's disease, Alzheimer's disease, and stroke. Furthermore, it has become increasingly evident that many environmental toxicants might contribute to the development of neurodegenerative disorders including Parkinson's disease. There is a complex balance between survival and apoptotic pathways in neurons derived from the central nervous system (CNS) that is distinct from non-neuronal cells or non-CNS neurons. The overall objective of our research is to identify signaling pathways that regulate neuronal apoptosis induced by various disease models as well as environmental toxicants. For example, our recent effort has focused on elucidating signaling mechanisms that regulate dopaminergic neuron cell death in relation to Parkinson's disease using exposure to several pesticides as model systems. It is our hope that these mechanistic studies may ultimately lead to the development of pharmacological interventions and clinical strategies for treatment of various neurodegenerative disorders and cancer. These studies may also provide insights concerning the relationships between environmental toxicants and the etiology of neurodegenerative disorders.
III. ERK5 IN CELL CYCLE REGULATION
Elucidation of mechanisms regulating cell cycle progression is of fundamental importance to Cell and Cancer Biology. Although many genes and signaling pathways have been implicated in G1/S regulation, less is known regarding mechanisms controlling the normal cell cycle progression through G2 and M phases. Besides a requirement for cyclin B and cdc2 activation, few other genes or signaling molecules have been identified that control the natural cell cycle progression through G2 and M phases. While studying the regulation and biological function of ERK5, we discovered a novel function for the ERK5 signaling pathway in regulation of the G2/M phase of the cell cycle. We are currently studying mechanisms underlying ERK5 regulation of G2/M, and the role of ERK5 in tumor growth.