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Director: Mark F. Mehler, M.D. Division Contact Information Mark F. Mehler, M.D. Phone: (718) 430-3543 e-mail: mark.mehler@einsteinmed.org

Mission

Our primary focus 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. Stem cells are also being utilized 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 progeny undergo irreversible cellular dysfunction and premature death or cellular transformation in response to acute or more chronic injury signals. Further, the knowledge gained from these multidisciplinary studies is being channeled into the design of innovative genetic, epigenetic and stem cell associated regenerative therapies. Research scientists 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. Institute investigators have identified specific transcription factor codes that endow the progeny of specific stem cell subpopulations with their unique cellular properties. These insights have already allowed us to "reprogram" specific regional stem and progenitor cell subpopulations both in vitro and in vivo to acquire the cellular properties of specific neuronal and glial subtypes. Specific complements of these discrete neural cell subtypes are invariably affected in different classes of neurological diseases including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and motor neuron disease/ amyotrophic lateral sclerosis, primary brain tumors, demyelinating and dysmyelinating disorders, stroke, HIV infection, epilepsy, diabetes mellitus and associated metabolic syndromes and premature aging.

Research Aims and Benifits

Other investigators 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 overall 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 in the adult brain. The ability to selectively activate, elaborate and modulate these latent developmental programs to participate in selective neural regenerative responses within discrete temporal intervals and spatial domains 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 Institute scientists to more effectively and selectively employ these emerging neural regenerative strategies. These approaches include elucidation of the complex and modifiable epigenetic code regulating interrelated genome-wide transcriptional networks using innovative gene microarray and related molecular technologies that identify and target primary DNA modifications, changes in the combinatorial properties of the histone code and precise alterations in the profiles and biological actions of multiple distinct classes of non-coding RNAs and other RNA-mediated pathogenic mechanisms. These studies will ultimately allow investigators to develop effective strategies to augment the endogenous stem cell response to injury or to cell transformation by the use of novel therapeutic modalities that:

1. Selectively enhance positive injury response cues (neuromodulatory cytokines and targeted transcription factors),
2. Concurrently promote the removal of inhibitory signals (inactivation of inflammatory cytokines and blockade of receptors that mediate inhibition of neurite outgrowth and axonal pathfinding by myelin and associated breakdown products),
3. Facilitate communications between the lesion site and the stem cell generative zones by enhancing the propagation of retrograde signals that establish morphogenetic gradients to enhance soluble factor signal transduction and also promote intimate cell-cell communications within functional compartments through the elaboration of selected classes of gap junction proteins (connexins) and other versatile intercellular signaling networks (e.g., Notch and integrin pathways) and
4. Facilitate genetic re-programming of transformed cells to promote the reestablishment of the mature differentiated phenotype.

Training Programs

Our division serves as an international educational resource for advanced training in stem cell biology and regenerative and epigenomic medicine with specialized graduate and postgraduate curricula and faculty scholar tracks currently serving trainees from Europe, North and South America, Africa and Asia through a variety of biomedical exchange programs. The aim of these broad and varied educational and training programs is to allow trainees to eventually return to their country of origin and to facilitate translation of these rapidly emerging experimental technologies into novel therapeutic applications and into creative collaborative partnerships in the areas of genetic epidemiology, bioengineering, computational biology, functional genomics and proteomics, advanced experimental therapeutics and numerous allied disciplines. We provide parallel training tracks to Einstein graduate students and medical scientist trainees, residents and fellows in neurology, neurosurgery, otorhinolaryngology, obstetrics and gynecology, pediatrics, psychiatry, internal medicine, cardiothoracic surgery and pathology. Moreover, we sponsor an early start scientific mentorship program to allow exceptionally motivated and gifted college and occasionally high school students to prepare for promising careers in biomedical research and translational medicine through summer and year-long intensive research exposures and national scholarship programs.

Collaborations

We are currently engaged in a wide variety of local, regional, national and international collaborations in the areas of developmental neuroscience, the pathogenesis of a spectrum of neurodevelopmental, neurodegenerative, neuroimmunological and neuropsychiatric diseases, neural regeneration and tissue remodeling, genetic reprogramming and epigenetics with an emphasis on the roles of non-coding RNAs in neural development and mature function, neurological disorders and neural network reconstitution following injury. Current collaborations of special note include an innovative epigenetics consortium established between the Institute and the ARC Special Centre for Functional and Applied Genomics and the Institute for Molecular Bioscience at the University of Queensland in Brisbane Australia (Professor J.S. Mattick) and the RIKEN Genomic Science Center and the RIKEN Yokohoma Institute in Yokohoma, Kanagawa, Japan (Professor Y. Hayashizaki) as an outgrowth of the FANTOM 3 Genome Project.