Our overall mission of The Saul R. Korey Department of Neurology is to develop subspecialty programs, centers and institutes of excellence to promote innovative comprehensive clinical care programs and complementary clinical, translational and basic science research programs to promote novel therapeutic strategies and eventually true disease cures through harnessing the unique and untapped potential of endogenous neural stem cell repair mechanisms, dynamic tissue remodeling and emerging genetic and epigenetic reprogramming strategies as well as emerging pharmacogenomic tools. We also have an essential responsibility to train the next generation of outstanding clinical neurologists, neurology subspecialty practioners, physician-scientists and basic science researchers in an atmosphere of intensive interdisciplinary cooperation between basic and clinical science departments, centers and institutes at Einstein, locally, nationally as well as internationally. A key intermediate term aim is to develop three interrelated Centers of Excellence and Innovation to help to rapidly advance our Departmental goals of clinical, scientific and educational leadership and vibrancy.
Proposed Einstein Centers of Excellence and Innovation
These centers will serve as vehicles for translating emerging conceptual and experimental biomedical advances and for fostering more integrative approaches to specific neurological diseases. Equally important, the centers will serve as bidirectional conduits, by also exploiting novel clinical discoveries to inform and modify basic science initiatives. Collectively, this model has the potential to dramatically accelerate the pace of discovery in the emerging area of neurological therapeutics and will distinguish Einstein from other leading national and international neurological disorders centers. This organizational approach mandates that these distinct but interrelated centers operate without walls.
I. Center for Endogenous Neural Repair
Overview: The unique biology of the nervous system with regard to three dimensional patterning, cell identity and connectivity requires the use of endogenous neural stem cells to promote selective, efficient, and enduring neural repair and associated tissue remodeling in response to all forms of neurological injury and disease. This novel approach will facilitate the re-establishment of the integrity of previously compromised neural networks by re-activating latent developmental programs and the cascade of molecular cues required for stem cell maturation, synaptogenesis and region-specific forms of synaptic plasticity and information processing. In contrast, traditional neural stem cell transplantation approaches have been uniformly unsuccessful in treating neurological conditions and are beset by complex scientific, social, geopolitical and moral issues.
The specific goals of this center are the following:
- To identify the site-specific injury signals (e.g., morphogens, cytokines, gap junction proteins, cell adhesion molecules, other transmembrane receptor-ligand subclasses) generated from acute (e.g., brain trauma, spinal cord injury, stroke, meningitis and encephalitis), subacute (e.g., demyelinating disorders including multiple sclerosis) and chronic (e.g., neurodegenerative diseases), injury and evolving disease states and involving specific neural subtypes (e.g., neuronal subtypes: neurodegenerative diseases; oligodendrocytes: multiple sclerosis; subacute injury: astrocytes).
- To identify the negative regulatory signals and their downstream cascades present at the injury site-associated neural stem cell generative zones and corresponding microenvironmental niches.
- To identify the underlying genetic and epigenetic mechanisms orchestrating developmental stage- and injury site-specific neural stem cell activation, expansion, migration, differentiation and incorporation into remodeled neural networks.
- Translation of these basic science insights into regenerative therapies (model organisms and ultimately patients) using peripheral delivery of stem cells and neurogenic cytokines that can cross the blood-brain barrier (short-term goal) and the development of small molecule biopharmaceuticals that selectively modulate progressive stages of stem cell lineage maturation through precise targeting of particular genetic and epigenetic signaling cascades (long-term goal).
II. Center for Genetic Reprogramming in Neuropsychiatric Disorders
Overview: It has recently become clear that gene-environmental interactions are critical not only for neural development, but also for the pathogenesis of a spectrum of neuropsychiatric disorders. An emerging body of knowledge suggests that the molecular interface governing gene-environmental interactions in health and disease is orchestrated by a wide variety of epigenetic mechanisms that significantly influence genetic transactions over different time frames, and provide a new class of targets for the development of unique therapeutic reagents. These particular therapeutic strategies will avoid the morbidity and mortality frequently associated with previous generations of pharmacological treatments and will also more effectively halt disease progression and eventually promote disease cures.
The specific goals of this center are the following:
- To identify the epigenetic influences (DNA methylation, histone codes, profiles of classes of non-protein coding RNAs, DNA and RNA editing) that result in specific classes of neuropsychiatric disorders.
- To identify strategies to correct disease-associated errors in DNA methylation, histone codes and associated chromatin remodeling and profiles and levels of expression of functional classes of non-coding RNAs.
- To identify strategies to promote dynamic recoding of disease-associated errors in DNA, RNA and proteins using specific DNA and RNA editing enzymes.
- To develop the technology for integrative human epigenotyping (DNA methylation, histone code modifications, expression of non-coding RNA subclasses and RNA and DNA editing).
- To translate these basic science insights into genetic reprogramming (model organisms and patients) using small molecule biopharmaceuticals.
III. Center for Neurological Disorders Across the Lifespan
Overview: The main focus of this center is to exploit the emerging links between alterations in neural development and the progressive elaboration of multiple classes of neurological disorders. The ability to identify specific molecular lesions during neural development that predispose to individual late-onset neuropsychiatric disorders will allow us to develop screening programs using more sensitive and earlier biomarkers and allied technologies (e.g., fMRI, MRS and PET imaging and neurophysiology and event-related potentials and cognitive assessment) based on insights gained through a wide variety of interdisciplinary basic science and translational research studies outlined in this proposal. This center will conduct research in the context of longitudinal follow-up in coordination with our affiliated health care delivery systems. Follow-up is necessary to observe and modify the unfolding of neurodevelopmental and degenerative disorders across the lifespan. This unique clinical care model will provide the foundation for a Neuropsychiatric Clinical and Translational Research Unit that will identify, recruit and further characterize specific patient populations, serve as a genetic and epigenetic discovery platform and biorepository and support innovative clinical trials and epidemiological studies for brain disease. Existing resources include East and West Campus GCRCs, the Gruss MRRC, the neurological intensive care units (being developed at Montefiore and Jacobi Medical Centers), the Clinical Research Center of the Einstein Aging Study and its affiliated biorepository, the Electronic Health Records (EHR) at our clinical affiliates and resident expertise in Epidemiology and Population Health. These resources will furnish much of the infrastructure required for the development and flexible implementation of this Unit.
A. Program in Developmental Disabilities and Human Genetics
This program will specifically utilize human genetic approaches to facilitate a detailed functional classification of neurodevelopmental disorders including mental retardation, autism spectrum disorders, attention deficit hyperactivity disorders, learning disorders and pediatric communication disorders and epilepsy. This evolving neurological nosology will guide the implementation of multidisciplinary molecular pharmacologic (see Centers I and II above) and cognitive and behavioral therapeutic strategies. This program will incorporate components of the clinical care model of CERC and the translational genetic model of the Clinical Genetic Screening and Counseling Program.
B. Program in Successful Brain Aging and Longevity
This program will utilize basic science and genetic epidemiological insights regarding the functional interplay between critical periods, brain plasticity, neural regeneration and genetic reprogramming to develop multidisciplinary approaches to forestall the onset and progression of neurodegenerative diseases, to augment cognitive reserve and to promote long-term healthy brain function and its consequences for the prevention of age-associated systemic disorders such as cancer, autoimmune and cardiovascular diseases.
C. Program in Chronic Disorders with Episodic Manifestations
Chronic disorders with episodic manifestations are characterized by attacks of clinical dysfunction with an enduring predisposition to attacks on an ongoing basis. Many common neurological and psychiatric disorders fit into this category including migraine, epilepsy, multiple sclerosis, stroke, sleep-wake disorders, addictive disorders, schizophrenia and depression. Most of these disorders begin early in life and often exhibit progressive, intractable forms that impose enormous public health burdens. This center will define the biological foundations underlying predisposition to attacks and the mechanisms that link the ictal and inter-ictal states. This program will build on existing expertise in headache disorders, epilepsy, stroke and sleep-wake disorders. Emerging evidence demonstrates that common episodic disorders often progress to become chronic and intractable in certain patient subgroups. Candidate genes have been identified and plausible mechanisms, including the development of sensitization and allodynia, have been defined. This program will develop multidisciplinary approaches to studying the mechanisms of chronic-episodic and progressive disorders of the developing, adult and the aging brain.