THE Albert EINSTEIN College of Medicine (AECOM) is a graduate school of Yeshiva University. It is a private medical school located in the Jack and Pearl Resnick Campus of Yeshiva University in the Morris Park neighborhood of the borough of the Bronx of New York City. AECOM also offers graduate biomedical degrees through the Sue Golding Graduate Division, in addition to the medical school. More than 200 faculty members perform biomedical research with an enrollment of nearly 400 graduate students. AECOM conducts research in basic biomedical science. The school receives more than $170 million annually in peer-reviewed grants from the National Institutes of Health. AECOM is affiliated with six hospitals: Montefiore Medical Center, Jack D. Weiler Hospital (a division of Montefiore Medical Center), Jacobi Medical Center, Bronx-Lebanon Hospital in the Bronx, Beth Israel Medical Center in downtown Manhattan, and Long Island Jewish Medical Center on Long Island.
Through its affiliation network, AECOM runs the largest postgraduate medical training program in the United States, offering over 150 residency programs to more than 2,500 physicians in training. The AECOM Department of Family and Social Medicine offers the Residency Program in Social Medicine (established in 1970), created to address the shortage of primary care clinicians trained to work in underserved communities.
The institute’s primary biomedical research 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 used 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 within the institute 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 institute scientists 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.
Other institute investigators have also used embryonic stem cells both to define the 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 important, 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 noncoding RNAs and other RNA-mediated pathogenic mechanisms.
These studies will ultimately allow institute 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 selectively enhance positive injury response cues (neuromodulatory cytokines and targeted transcription factors), concurrently promote the removal of inhibitory signals (inac-tivation of inflammatory cytokines and blockade of receptors that mediate inhibition of neurite outgrowth and axonal pathfinding by myelin and associated breakdown products), 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 transduc-tion 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 facilitate genetic reprogramming of transformed cells to promote the reestablish-ment of the mature differentiated phenotype.
