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Shared Facilities for Stem Cell Research III - 2013

RFA # 1121110215


PI Institution Budget
Einstein Shared Facilities for Stem Cell Research Paul Frenette Albert Einstein College of Medicine $3,557,019
Large-Scale Biochemical Profiling for Stem Cell Research in New York Lewis Brown Columbia University $1,194,346

Cornell Stem Cell Modeling and Phenotyping Core

John Schimenti Cornell University $3,027,175
Imaging Stem Cells in the Brain for Studying Neuropsychiatric Disorders René Hen New York State Psychiatric Institute $3,078,827
NeuraCell Chris Bjornsson Regenerative Research Foundation $2,299,970
The SKI Stem Cell Research Facilities Mark Tomishima Sloan-Kettering Institute $3,508,315
A Shared Facility for the Derivation, Validation, and Distribution of Stem Cells for Disease Modeling Todd Evans Weill Cornell Medical College $3,334,348

For more information on NYSTEM-supported facilities, visit our Shared Facilities page.

Einstein Shared Facilities for Stem Cell Research

Paul Frenette, M.D.
Albert Einstein College of Medicine

Einstein Shared Facilities for Stem Cell Research provide services to promote pluripotent and somatic stem cell research, enhance epigenetic and genetic analyses in single stem cells, and facilitate in vivo stem cell transplantation. These cores allow users to benefit from high-quality, state-of-the-art services that could not be achieved in individual laboratories. The goals of these facilities are to: i) to provide human pluripotent stem cells (PSC) for studies of directed differentiation, self-renewal, and/or disease mechanisms (PSC Core); ii) to provide facilities and expertise for stem cell isolation and assays for in vivo transplantation of human somatic or PSC-derived cells in immunodeficient mice (Stem Cell Isolation and Xenotransplantation Core); and iii) to provide epi/genomic assays and computational analyses for few or single stem cells (Single-Cell Genomics Core). Over the last four years, the PSC Core has served 10 to 15 researchers per year and trained several users in PSC culture methods or induced pluripotent stem cell production methods. The Stem Cell Isolation and Xenotransplantation Core has provided advanced multiparameter cell sorting dedicated to stem/cancer cell users and highly skilled in vivo transplantation or sampling assays in mice or rats to test the function of somatic or pluripotent stem cells. The Core has ongoing collaborations with the New York Stem Cell Foundation, other NY State academic centers, the Eastern Cooperative Oncology Group and pharmaceutical companies to study cancer, bone repair and multiple sclerosis. We are expanding the core offerings to include epi/genomics analyses for single or few cells to address common problems facing stem cell researchers working with rare populations of stem cells. This innovative Core will also offer expert computational analyses of large datasets, as these highly specialized analyses remain out of the reach of most stem cell laboratories. These Cores will lay the groundwork for the translation of scientific discoveries toward regenerative medicine.


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Large-Scale Biochemical Profiling for Stem Cell Research in New York

Lewis Brown, Ph.D.
Columbia University

In New York State there are shared facilities that support stem cell research from a variety of perspectives.  Even with substantive institutional infrastructure, full application of the benefits expected from post-genomic biology is being impeded by a lack of certain infrastructural components. In particular, we lack the ability characterize the metabolism of stem cells, and to fully understand the metabolic and protein modification changes that occur as a result of manipulations such as the induction of pluripotency or differentiation. 

The large-scale study of the global sets of small molecules in cells is called metabolomics. Metabolomics is expected to have a transformative impact on the understanding of stem cell fate and physiology, as well as patient care in regenerative medicine. Concentrations of metabolites cannot be deduced from genomic information. This requires dedicated, high-sensitivity, non-targeted unbiased screening not generally available at Columbia University and in New York State. Posttranslational modifications of proteins are also important drivers of development and physiology of stem cells. Analogous to the situation in studying the metabolome, the identities and concentrations of these modified proteins cannot be deduced from genomic information. To address both problems we will acquire a new liquid chromatograph-mass spectrometer and increase staffing level to support this equipment.

Twenty-two major facility users who are New York State principal investigators on actively-funded, peer-reviewed stem cell research projects are presently conducting 32 stem cell research projects supported by federal grants, private foundations and NYSTEM. Each of these projects has been carefully selected for its scientific impact and its potential for worthwhile utilization of the proposed resource. These researchers represent eight New York State institutions, and the resource is planned to continue to be available to researchers statewide.

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Cornell Stem Cell Modeling and Phenotyping Core

John Schimenti, Ph.D.
Cornell University

Stems cells are crucial for normal life functions, certain diseases, and have great promise for treating various illnesses and birth defects. To determine how stem cells work and to exploit them for scientific and medical ends, advanced animal models and analytical capabilities are essential. However, the requisite specialized expertise and instrumentation is beyond the capabilities of most academic laboratories. Consequently, shared facilities are critical to the stem cell research enterprise.

Our facility will provide state-of-the art capabilities for NY scientists to: generate stem cells, modify genes in highly specific ways, create transgenic research animal models for basic and clinical research, analyze pathology of these animal models with high diagnostic and microscopic resolution, and study individual stem cells in live animals or in manmade environments. 

Our ability to understand stem cell properties, the genetic mechanisms underlying these properties, and to utilize them for regenerative medicine requires sophisticated animal modeling. The most powerful and practical animal model is the mouse, which has biology and genetics similar to humans. The facility will produce custom mice and stem cells with precisely engineered genes, and it will support similar experiments in other species for veterinary, agricultural and disease modeling purposes. The facility will also have a pathology component to expertly study these and other disease models, as well as an advanced microscopic imaging component for high resolution visualization of stem cells in natural or manmade microenvironments. Lack of such highly specialized resources represents a barrier for most scientists, due to the expense of instrumentation and resources needed for these capabilities. The expertise, resources, and instrumentation in this Facility will enable academic researchers to conduct advanced stem cell experiments expeditiously.

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Imaging Stem Cells in the Brain for Studying Neuropsychiatric Disorders

René Hen, Ph.D.
New York State Psychiatric Institute

In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus (DG). The DG is a subregion of the hippocampus that has been proposed to play a role in pattern separation, a process by which similar experiences or events are transformed into discrete non-overlapping representations. Preliminary data from our labs suggest that aged mice and anxious mice display pattern separation deficits, and that hippocampal function and pattern separation may be impaired across several disease states. These include mild cognitive impairment (MCI) and several severe anxiety and mood disorders, including posttraumatic stress disorder (PTSD), panic disorder, and Major Depressive Disorder. We propose that impaired pattern separation (or excessive generalization) is an endophenotype of these disorders and we hypothesize that increasing human hippocampal neurogenesis by pharmacological means will improve pattern separation-related impairments.

The overarching goal of this facility is to study the properties of neural stem cells and their progeny in order to be able to harness these properties to improve mood and cognition in various patient populations. To achieve this goal we will create an Imaging Core Facility that will enable us to study neural stem cells and their progeny both in vitro and in vivo. Specifically we propose to implement two novel technologies: 1. CLARITY is a system that allows imaging the whole brain of mice and men without sectioning them and will therefore be ideal to study the connectome of stem cells and their progeny; 2. We will use a recently developed technology to image stem cells and their progeny in live mice in order to understand the contribution of these cells to specific learning and anxiety-related behaviors.

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Chris Bjornsson, Ph.D.
Regenerative Research Foundation

Neurological disease causes great burden to patients, families and our healthcare and social service systems. Damaged nervous system tissue has limited regeneration and repair so that loss of function is often chronic and unrelenting. Research using neural stem cells (NSCs) provides a needed platform to advance therapeutics for these devastating disorders. It is essential that researchers have a ready source of well-characterized, stable and verified NSCs to work with. The nervous system is unique in its complexity: each region contains specialized cell types. Spinal cord motor neurons that are lost in spinal cord injury are distinct from pyramidal neurons, which die in Alzheimer’s disease, or the oligodendrocytes that are lost in multiple sclerosis. Consequently, one of the great challenges for nervous system repair is to produce the variety of neural cell types. In 2009, through an investment by the NYSTEM program, we launched NeuraCell, a shared resource facility aimed at bringing our expertise and experience with NSCs to other researchers. In just over three years, NeuraCell has become a vibrant and thriving hub that supports NSC research throughout NYS. NeuraCell strengthens our growing community of NSC scientists, assisting researchers to achieve their short-term goals of data-generation for projects and grant applications, and to progress toward the long-term goal of generating stem cell-based therapies. NeuraCell functions as a central core providing specialized stem cell knowledge, training, a variety of NSCs, and stem cell culture reagents. Here we propose to expand and continue the operation of NeuraCell by increasing the infrastructure and visibility, and offering new services that play off the strengths of those already established. NeuraCell has positioned itself as a facilitator of stem cell research, and its continued operation will allow many institutions to benefit from cutting edge, stem cell products and services.

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The SKI Stem Cell Research Facilities

Mark Tomishima, Ph.D.
Sloan-Kettering Institute for Cancer Research

The SKI Stem Cell Research facility provides a number of key services to the NYS stem cell community. We maintain a well-curated human pluripotent stem cell (hPSC) library and teach interested scientists how to culture the cells. To date, >80 scientists from 23 institutions have enrolled in classes from our facility. In addition to our hPSC library, we provide a reprogramming service that makes human induced pluripotent stem cells (hiPSCs) on demand. Our facility has achieved a few "firsts" in genetic modification of hPSCs, and we provide a number of genetic modification solutions to our client labs. The facility was part of publications that described the first use of bacterial artificial chromosome (BAC) transgenics, increases in gene copy number through BACs, and the first use of non-viral, ZFN-enhanced homologous recombination. One of the other important services that we provide is directed differentiation into specific cell types. Here, we propose to extend our expertise in this area by providing additional hPSC-derived cell types as quality-controlled, cryopreserved aliquots that can be shipped to any lab.

Our facility is also part of a consortium that is attempting to bring hESC-derived midbrain dopamine neurons to medical applications as a treatment for Parkinson's disease. We hope to share this expertise with other NYS stem cell researchers by offering an integrated solution for translation. Our facility will make available two dedicated cGMP rooms in our new MSKCC cell production facility to NYS investigators for stem cell-based projects. It will also provide them with information on how to transition a research-grade protocol to a GMP process, both through new classes and hands-on help. NYSTEM has previously supported an NY upstate cGMP facility, but having this expertise available to investigators in NYC and NY downstate region will help to accelerate clinical applications of stem cells. 

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A Shared Facility for the Derivation, Validation, and Distribution of Stem Cells for Disease Modeling

Todd Evans, Ph.D.
Weill Cornell Medical College

We will establish a new cross-Institutional Shared Research Facility to derive and distribute human and mouse embryonic stem cell (ESC) lines as tools for preclinical development of new therapies for human diseases. There is great potential for using ESCs to treat human diseases that cause great suffering and overwhelm our health care system, including diabetes, neurodegenerative syndromes, and liver or heart failure, for example through regeneration with normal ESC derivatives. We can make patient-specific cells (iPSCs), possibly overcoming issues of immune rejection. However, there remain many barriers to the effective use of cell-based regenerative therapies. Most if not all ESC derivatives are relatively immature and may not integrate in a disease setting. The cellular basis for the disease is often incompletely understood in the first place. Even before ESCs and patient-specific iPSCs are ready for cellular therapies, they can already be used for modeling the disease “in a dish” and for testing drugs in toxicity or differentiation assays. However, disease-modeling technology using ESCs and iPSCs requires access to unique cell lines and special expertise. We have organized a collaborative consortium of investigators and staff that have unmatched access to cell lines and a strong track record of expertise in these areas. Collaborating across three major biomedical campuses, closely located to each other in New York City, we will create, bank, and provide new disease-associated lines and other tools for disease modeling that can be used immediately by ourselves, our colleagues, and other investigators in New York State to better understand human diseases and to develop novel therapeutics. We will provide cell lines and differentiated cells. Using new gene engineering approaches, we will create specific gene mutations and use optimized differentiation protocols to compare phenotypes. The cellular products will provide unique tools to significantly enhance the capacity for development of cellular therapeutics. 

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