The primary focus of our laboratory is on defining the regional localization and the biological properties of neural stem cells during embryonic and postnatal development and in the mature and the aging mammalian brain. We are also using stem cells as "biological probes" to elucidate the pathogenesis of a spectrum of complex and poorly understood acquired and genetic nervous system disorders. In these prototypical disorders, distinct profiles of regional stem cells or their more lineage-restricted neuronal or glial cell progeny undergo irreversible injury and death in response to acute or more chronic injury signals.
Further, we are attempting to use the knowledge gained from these multidisciplinary studies to design innovative gene/epigenetic- and stem cell-based regenerative therapies. We are in the process of defining the dynamic roles of environmental factors, cell-cell signaling pathways and cell autonomous cues in promoting stem cell activation, expansion, lineage restriction, lineage commitment, cell cycle exit and terminal differentiation. We have identified specific transcription factor codes that endow the progeny of specific stem cell subpopulations with their unique cellular properties and cell identity.
These insights have already allowed us to "reprogram" different regional stem and progenitor cells both in vitro and in vivo to acquire the cellular properties of specific neuronal and glial subtypes that are lost in different classes of neurological diseases. We have also utilized embryonic stem cells, both to define initial stages of neural induction and patterning of the neural tube that have previously been difficult to examine experimentally, and as therapeutic reagents for those diseases of the nervous system in which multiple regional neuronal and glial subtypes are targeted. The ultimate aim of these studies is to identify innovative approaches to brain repair by activation of latent neural stem cell pools throughout the neuraxis to engage in selective regeneration of those cell types and neural network connections that have been compromised in specific disease states. The ability to activate and recruit these latent developmental programs to participate in selective neural regenerative responses will help to reestablish functional neural networks that preserve the integrity of previously acquired informational traces.
More importantly, a better understanding of the pathogenesis of individual neurological disorders will allow us to more effectively employ our emerging neural regenerative strategies. For example, we are investing the paradigm shifting possibility that early developmental abnormalities are important in the etiology of disorders of the aging brain, namely neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's Diseases. In these diseases of the “aging brain”, we have uncovered a spectrum of impairments in neural induction, patterning of the neuraxis and regional stem cell-mediated neurogenesis and gliogenesis that persist throughout life. These abnormalities in the stem cell niche, migratory pathways and microenvironment associated with cellular differentiation, maturation and maintenance functions create “developmental stress responses” that promote relaxation of epigenetically-mediated lineage constraints, thereby promoting context-specific cellular vulnerability to the triad of disorders of aging: neurodegeneration, cancer and fibrotic disorders. Moreover, our experimental findings have shown that neurodegenerative pathogenic mutations also impair earlier stages of embryonic stem cell maintenance, germ layer formation, organogenesis and organ- and tissue-specific cell lineages. These findings provide a biological basis for the epidemiological and pathological associations between specific neurodegenerative diseases, cancer subtypes and organ fibroses as well as a common biology and mechanisms mediating organ- and site-specific brain metastatic tropism and the uniqueness of the brain substrate for preventing peripheral metastatic engraftment of even the most aggressive brain tumors.
