2001 — 2002 |
Svendsen, Clive Niels |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Core--Animal Care and Breeding @ University of Wisconsin Madison
DESCRIPTION: The Animal Care Core provides husbandry as well as breeding and record keeping in support of all animals used by Center projects, and is dedicated to the needs of Center investigators. For mice, this includes making available a wide variety of mutant lines at specific ages and raised in specialized rearing conditions. Other species also covered in this Core are said to be rats, cats, hamsters, rabbits, and frogs.
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0.978 |
2004 |
Svendsen, Clive Niels |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Vervet Embryonic Stem Cells For Studying Parkinson's @ University of Wisconsin Madison
embryonic stem cell; Parkinson's disease; Cercopithecidae; animal colony;
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0.978 |
2005 — 2008 |
Svendsen, Clive Niels |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Stem Cell Research Training Program @ University of Wisconsin Madison
DESCRIPTION (provided by applicant): We propose to establish an interdisciplinary postdoctoral training program for all aspects of research into the biology of stem cells. A major strength of this program is the range of expertise at University of Wisconsin in stem cell biology - from basic embryology, through clinical trials, to ethics and policy research. Postdoctoral trainees from specific areas of developmental biology, neuroscience, endocrinology, blood science, heart science, bioengineering, and other specialties such as policy and ethics will enter this program and be matched with the primary mentor appropriate for their area of interest. In addition, there will be opportunities to study the ethical implications of stem cell research. Key aspects of the program include (i) establishing mentor committees with direct interest in stem cell biology, (ii) encouraging active interactions with other laboratories involved with stem cell research through seminars, journal clubs, workshops, and retreats, (iii) attending UW-Madison courses related to stem cell biology and research ethics, and (iv) interacting with the key institutes on campus which have become central to stem cell biology, including the Biotech Center, Waisman Center, Primate Center, and the non profit organization WiCell. The trainees will participate in a number of newly developed courses in stem cell biology - from basic principles to applications. They will be made aware of the huge commercial implications of stem cell biology and the latest thinking on translating this potential into clinical trials. The investigators aim to train a future generation of principal investigators within this important new field. All laboratories in this program which work with human embryonic stem cells will continue to use only Federally-approved cell lines, specifically WA01, WA07, WA09, WA13, and/or WA14.
|
0.978 |
2005 |
Svendsen, Clive Niels |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Derivation of Vervet Embryonic Stem Cells For Studying Parkinson's Disease @ University of Wisconsin Madison |
0.978 |
2006 |
Svendsen, Clive Niels |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Derivation of Embryonic Stem Cells For Studying Parkinson's Disease @ University of Wisconsin Madison |
0.978 |
2007 — 2011 |
Svendsen, Clive Niels |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Astrocytes Producting Growth Factors For Als @ University of Wisconsin Madison
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder for which there is no effective treatment or cure. The long term objective of part of the program project application is to develop new lines of human progenitors releasing growth factors that can be used in pre clinical studies towards a cell based therapy for ALS. The specific hypothesis is that progenitors engineered in vitro to produce growth factors will generate astrocytes when transplanted which then slow down or prevent motor neuron death in a rat model of ALS. This is based on extensive published data showing that there may be a primary deficit in astrocytes in both patients and rodent models of ALS and that growth factors can protect motor neurons from cell death. Our preliminary data shows that we can generate human neural progenitors that secretegrowth factors, and that these can survive, migrate and integrate into the spinal cord of the ALS rat, forming a human/rat chimera. Based on these observations the specific aims are 1. Improve and extend our current progress in protecting motor neurons in the ALS rat using novel approaches including regionally specified astrocytes, drugs to block inflammation, and species specific astrocytes. 2. Perform further experiments using new lines of progenitor cells releasing growth factors recently shown to have strong protective effects on motor neurons. 3. Extend our studies to the phrenic motor complex in collaboration with Dr. Mitchell (Project 1) and assess whether astrocytes releasing growth factors can prevent changes in respiration related to motor neuron loss. The results of these experiments will establish whether astrocyte transplants combined with growth factor delivery can ameliorate motor neuron death in a well established model of ALS. As such they constitute a highly relevant set of experiments to national health. The information will also be crucial to the other projects in this program - through providing growth factor secreting astrocytes to protect respiratory motor neurons (Project 1) and human motor neurons derived from ES cells (Project 3).
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0.978 |
2007 — 2011 |
Svendsen, Clive Niels |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Stem Cell Therapy and Growth Factor Therapy For Als @ University of Wisconsin Madison
[unreadable] Description (provided by applicant): ALS is a devastating disease causing progressive motor neuron degeneration and death. Most ALS patients develop severe respiratory insufficiency and, ultimately, die from ventilatory failure. Despite its fundamental mportance, respiratory function has seldom been studied in any ALS model. In this revised application, we focus attention on respiratory motor function in a rodent model of familial ALS, the transgenic rat overexpressing mutated superoxide dismutase-1 (SOD1G93A rat). The fundamental hypothesis guiding this proposal is that compensatory spinal neuroplasticity offsets severe motor neuron degeneration, preserving the ability to breathe until late in disease progression. We propose to investigate mechanisms of compensatory spinal plasticity in SOD1G93A rats, and to determine if further plasticity can be induced with ghronic treatments that enhance respiratory plasticity, such as intermittent exposures to low oxygen (hypoxia). We also propose to investigate the contributions of key trophic factors postulated to play key roles in respiratory plasticity or ALS pathogenesis: brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). To achieve our primary goal, four specific hypotheses will be tested: 1) SOD1G93A rats utilize compensatory spinal neuroplasticity to preserve ventilatory function despite severe inspiratory motor neuron cell death; 2) daily intermittent hypoxia enhances respiratory plasticity and actually delays disease progression; 3) serotonin-dependent BDNF regulation underlies compensatory respiratory plasticity during ALS; and 4) VEGF improves respiratory motor output and motor neuron survival. Our perspective is unique, focusing on compensatory mechanisms that offset progressive motor neuron degeneration, thereby preserving function in a critical, homeostatic motor system. The utilization of diverse and highly innovative experimental approaches (e.g., RNA interference in vivo; and transplantation of neural progenitor cells secreting trophic factors), the extensive experience of the laboratory with all aspects of this proposal, and exciting preliminary data increase the likelihood that the proposed experiments will significantly advance our understanding of ALS. Collectively, these aims will provide unique insights concerning the progression of familial ALS (and other forms by inference), and may provide the rationale for novel therapeutic strategies for a neurodegenerative disease with no known cure. [unreadable] [unreadable] [unreadable]
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0.978 |
2007 |
Svendsen, Clive Niels |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Adminstrative Core @ University of Wisconsin Madison |
0.978 |
2007 — 2011 |
Svendsen, Clive Niels |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Histology &Imaging @ Cedars-Sinai Medical Center
The histology and imaging core will provide essential services to the three projects that make up this program project grant. Specifically, it will section spinal cord specimens, store sections, perform routine immunohistological stains, perform routine tracing, histological stains and establish new protocols where needed. The Core will provide for the skills and equipment necessary to perform imaging and complex stereological counts and confocal analysis of transplants in the spinal cord. This equipment is expensive and highly specialized, thus making such a shared arrangement more practical. Dr. Dan Peterson will serve as a consultant in the operation of this core, thereby adding considerable expertise pertaining to confocal and sterology applications;he will also help with the interpretation of spinal cord transplants. The experiments carried out within the program project could not be done efficiently without the services of the Histology and Immunology Core (Core B).
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0.978 |
2008 — 2009 |
Svendsen, Clive Niels |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Directing the Fate of Neural Stem Cells With Engineered Gradients of Fgf-2 @ University of Wisconsin Madison
[unreadable] DESCRIPTION (provided by applicant): The therapeutic use of human neural stem cells (hNSC) to treat neurological disorders or injuries depends upon the ability to direct stem cell differentiation into the relevant cell types, with the same overall architecture as the corresponding in vivo tissue. Gradients of biological molecules, called morphogens, are pervasive throughout human development and help direct cell differentiation as well as the position of different cell types within the fully formed human. In the early cerebral cortex, FGF-2 gradients are thought to have an important role in establishing the cell types and tissue architecture that are essential for ultimate biological function. Capitalizing on recent advances in microfluidic technology, we will apply different FGF-2 gradients to hNSC cultures to examine if FGF-2, when presented as a gradient, can induce hNSCs to recapitulate in vitro the various cell types and tissue architecture observed in vivo. Time lapse phase and fluorescence microscopy will be used in conjunction with immunocytochemistry to examine the effects of FGF-2 gradients on cell cycle, fate, size, position, proliferation, and migration. We predict that with the appropriate FGF-2 gradient, high FGF-2 regions will contain mostly mitotic hNSCs that divide symmetrically to form more mitotic hNSCs. Regions with slightly lower FGF-2 concentrations will be populated with more asymmetrically dividing hNSCs that begin to generate neurons. Regions with yet lower FGF-2 concentrations will generate only neurons, where local FGF-2 concentration causes hNSCs to generate neuronal cell types specific to certain layers of the cortex. The study that we have proposed is the first to investigate a specific event in human development by culturing human stem cells in a microfluidic device that recreates the types of chemical microenvironments observed within the developing fetus. We believe the proposed study will yield great insight into human neural development and will make a significant step forward towards developing functional in vitro neural tissue from human stem cells. PUBLIC HEALTH RELEVANCE Understanding how the part of the brain that gives humans their unique cognitive abilities initially forms is important for understanding the cause of many disorders and diseases of the brain. The ability to direct stem cells to replicate the types of cells and the arrangement of those cells observed within the human brain would greatly advance our ability to treat brain disorders, diseases, and injuries. [unreadable] [unreadable]
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0.978 |
2008 — 2009 |
Svendsen, Clive Niels |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. |
Sharing in the Discovery Stem Cell Learning Lab @ University of Wisconsin-Madison
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To inform and educate the public about stem cell and regenerative medicine research at the UW-Madison. To engage teachers and students and provide resources and ideas for incorporating stem cell and regenerative medicine studies into science education curricula. To work with the new (2009) UW-Madison Office of Science Outreach to publicize the program and help teachers and others find our service and schedule visits to the lab. This is a continuing collaborative effort among the UW-Madison Stem Cell and Regenerative Medicine Center, Biotech Center, Primate Center and their outreach partners throughout Wisconsin. The project leader is Jordana Lenon, B.S., and she employs a student hourly lab manager. In 2008-2009, we successfully set up a stem cell learning lab for the public at the Genetics-Biotechnology Center, to serve the public, students grades 4-12, college students, minority programs, alumni, retirees, and other "lifelong learners." Visitors view an introductory talk, ask questions and discuss research and current issues. Then, the groups work in a lab using real lab techniques and equipment, with simulated cells and media due to biosafety issues. They are able to observe real live ES and iPS cells from James Thomson's lab. (We acquire the live cells in the morning, before the groups arrive.) Many groups then visit the Primate Center and learn about its important role in UW-Madison stem cell history and current research. Lab setup occurred early in 2008, the first groups began visiting in April 2008. To date, our lab experiences have drawn more than 1,000 visitors. We have also taken the experience to UW-Madison's Science Expeditions, and on the road, to venues including Farm Technology Days in Brown County, and the Wisconsin State Fair in Milwaukee County. Through this project, we have also scheduled UW-Madison stem cell and regenerative medicine speakers to present to numerous audiences about this broad scientific field. Our speakers have included principal investigators, post-doctoral trainees and graduate students. This project relies on the time and resources of the WNPRC Public Information Officer, who is also a university relations specialist for the Stem Cell and Regenerative Medicine Center. This project uses federally approved human embryonic stem cell lines obtained from James Thomson's lab.
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0.978 |
2009 — 2010 |
Finkbeiner, Steven M (co-PI) [⬀] Gusella, James F Ross, Christopher A (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
RC2Activity Code Description: To support high impact ideas that may lay the foundation for new fields of investigation; accelerate breakthroughs; stimulate early and applied research on cutting-edge technologies; foster new approaches to improve the interactions among multi- and interdisciplinary research teams; or, advance the research enterprise in a way that could stimulate future growth and investments and advance public health and health care delivery. This activity code could support either a specific research question or propose the creation of a unique infrastructure/resource designed to accelerate scientific progress in the future. |
The Huntington's Disease Ips Consortium @ University of California-Irvine
DESCRIPTION (provided by applicant): This consortium aims to capitalize on an unprecedented "grand" opportunity to develop a novel and powerful model of Huntington's disease (HD), a fatal neurodegenerative condition with no current treatment. Skin cells from patients with HD can be reprogrammed to pluripotency and then differentiated into specific neuronal and glial cell types, permitting investigation of the effects of the genetic lesion in the susceptible human cell types. We hypothesize that the genetic changes that cause HD lead to specific alterations in neuronal function- perhaps even survival-that will give important clues as to the mechanism and progression of disease. Altered cellular phenotypes will also serve as the foundation for translational research and drug development. Stimulus funding will bring together a highly focused group that (i) has a strong track record of innovative HD research and of working together, (ii) is poised to engage in cutting-edge research with recently generated induced pluripotent stem (iPS) cells derived from HD patients and is committed to broad distribution of findings, protocols and iPS lines, (iii) can capitalize on this stimulus funding through further grant applications and collaborative studies, and (iv) is partnered with CHDI, an HD foundation with dedicated HD stem cell and translational/drug discovery programs. This infusion of funds will accelerate the coordinated analysis of iPS lines and leverage the complementary, synergistic skill sets that will move the field forward more rapidly than would be possible by any group alone. The proposed studies will provide an entirely novel genetically accurate model to test new drugs in the fight against this disease, a unique resource that will benefit the entire HD community. PUBLIC HEALTH RELEVANCE: We hypothesize that the genetic changes that cause Huntington's disease lead to specific alterations in neuronal function-perhaps even survival-that, in turn, give important clues as to the mechanism of disease and its progression and offer a potential basis for small molecule screening assays. Our studies will provide a more authentic way to study the consequences of the HD mutation in human target cells. They represent a unique and timely opportunity to enhance the investigation of disease mechanisms and will generate a validated resource freely available to the HD community to further accelerate HD research toward a successful treatment.
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0.946 |
2012 |
Svendsen, Clive Niels Town, Terrence C [⬀] |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
An Ips Disease-in-a-Dish Model of Familial Alzheimers @ Cedars-Sinai Medical Center
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of amyloid-¿ peptides as 'senile' ¿-amyloid plaques, neurofibrillary tangles comprised of abnormally phosphorylated tau protein, and neuronal dysfunction and loss. Currently available AD treatments have a quantitatively minor impact on the disease, doing little to improve the quality or duration of life of patients suffering from thi debilitating illness, which is clinically characterized by loss of pneumonic and higher cortical functions. A critical lynchpin for the development of an AD treatment that is both effective and safe is model systems that faithfully recapitulate the human syndrome. In this regard, transgenic mice harboring mutations in one or more genes that cause early-onset familial AD (fAD) have been enormously helpful, both in terms of interrogating potential therapeutic targets and also for understanding pathological mechanisms of disease. Yet, these models are necessarily limited due to their species, and it remains an open question as to whether the mouse will ever be able to faithfully model AD neuropathology as it occurs in the human. The central theme of our R21 grant application is to use an emerging technology with great promise for modeling human diseases: human induced pluripotent stem (hiPS) cells. The basic steps involve culturing skin fibroblasts from individuals bearing mutations in genes that cause fAD or from age-matched control relatives lacking disease, and reprogramming them into hiPS cells that are later differentiated into forebrain glutamatergic neurons. Once differentiated, these forebrain neurons will be functionally interrogated to specifically assess pathologic hallmarks of human AD. We propose to carry out this work in two parts. The focus of Specific Aim 1 is to establish iPS cell lines from four fAD mutant and four related control fibroblast cell lines. We will draw fibroblasts from ~175 lines derived from individuals bearing fAD mutations and age-matched control relatives, maintained through the NIH/NIA Aging Cell Culture Repository at the Coriell Institute for Medical Research. The main goal of Specific Aim 2 is to interrogate Alzheimer phenotypes in fAD mutant vs. control forebrain neurons differentiated from reprogrammed iPS cells. In Sub-Aim 2a, we hypothesize that Alzheimer disease phenotypes will occur and be exacerbated by experimental induction of excitotoxicity in fAD mutant vs. non-mutant hiPS-derived forebrain neurons. Sub-Aim 2b will test proof-of-concept for whether the current standard of care AD drug, memantine, will at least partially rescue Alzheimer phenotype(s) in differentiated fAD mutant forebrain neurons. Completion of this exploratory work is expected to lead to a 'disease-in-a-dish' model of human fAD. Such a model could pave the way toward understanding both basic pathologic mechanisms of the disease as well as potential therapeutic approaches. PUBLIC HEALTH RELEVANCE: There are now over 3 million Americans afflicted with Alzheimer's disease, a figure that is projected to increase to 9 million by 2050, underscoring a rapidly developing public health crisis. We propose to utilize cutting-edge human induced pluripotent stem (hiPS) cell technology to model this devastating disease in cultured neurons. If successful, this exciting disease-in-a-dish model could allow pre-clinical testing of therapeutic approaches.
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0.928 |
2014 — 2017 |
Finkbeiner, Steven M (co-PI) [⬀] Fraenkel, Ernest (co-PI) [⬀] Rothstein, Jeffrey D (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Administration - Neuron and Glial Cellular Signatures From Normal and Diseased Ips Cells @ University of California-Irvine
Administration Component The Administrative Core is responsible for setting the overall direction of the NeuroLINCS center and for ensuring that the resources and components of the Center are optimally utilized. The successful development and evolution of the NeuroLINCS center requires strong interactions between the leaders and co-leaders of each Component and of the center as a whole. Hence, the NeuroLINCS Administrative Component plays a vital role in facilitating these interactions. Moreover, the Administrative Component and its personnel provide the necessary administrative and fiscal oversight to ensure that the NeuroLINCS center is run efficiently. The NeuroLINCS center involves 5 principal sites with defined responsibilities of growing, differentiating and generating new induced pluripotent stem cell lines (iPSCs), performing data generation assays on human brain cells made from iPSCs in response to perturbagens, performing basic analyses and developing cell signatures through integrated data analysis .methods, and establish community interactions. An integrated and highly collaborative group of investigators with expertise in stem cell biology, IPS cells, quantitative molecular phenotyping (omics and single cell imaging) and bioinformatics will work closely together to generate significant and highly predictive cell signatures. The PIs of the NeuroLINCS center are Steven Finkbeiner (Gladstone), Ernest Frankel (MIT), Jeffrey Rothstein (JHU), Clive Svendsen (Cedars) and Leslie Thompson (UCI), who will serve as leaders and co-leaders of components. Each Component has identified co-investigators/collaborators/consultants appropriate for the planned scientific investigations. Component leaders and co-leaders will also be active participants in NeuroLINCS consortium working groups as they are developed to address specific issues. Results of the genetic, proteomic and other characterization conducted by consortium labs will provide important feedback for further enhancement of induction and differentiation protocols and related methodologies and it is anticipated that this collaborative and iterative approach will lead to the broadest success for the study. An Evaluation Program within the NeuroLINCS is in place to determine if the programs supported are meeting the needs of the research community, are efficiently managed, and demonstrably effective and annual objectives and milestones.
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0.946 |
2014 — 2017 |
Finkbeiner, Steven M (co-PI) [⬀] Fraenkel, Ernest (co-PI) [⬀] Rothstein, Jeffrey D (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Data Generation Core - Neuron and Glial Cellular Signatures From Normal and Diseased Ips Cells @ University of California-Irvine
Data Generation Component We propose three broad experimental aims based around the type of assay, perturbagens and technologies being applied that will overlap across the years. The first will use iPSCs from three disease states (non affected, SMA and ALS) in which we have shown specific phenotypes. We will use an iterative approach by first screening for a number of perturbagens of interest to the broad neuroscience community using cost effective assays including simple cell death models and a highly novel imaging analysis system. The second parallel effort will be to use the same iPSC lines but in this case test a set of known cell modifiers (Glutamate, ER stressor and SOD1 ASO) as perturbagens and perform massive parallel quantitative molecular phenotyping (QMP) to generate robust signatures and to define the responses of motor neuron cultures to these perturbagens. We will then perform QMP on neurons, astrocytes and oligodendrocytes from disease and control cells and in response to the same perturbations as above to elucidate signatures across broadly relevant neural cell types. This data will be compared to motor neuron cultures (where expected disease signature will be) with non motor neuron cultures (where no or a more restricted disease signature is expected) to resolve the question of cell type specificity. We will also generate new iPS lines from post mortem human patient tissues to allow clinical pathological signatures to be incorporated into the LINCS data, providing a unique resource to both the SMA and ALS scientific community and to researchers interested in larger questions relating to the CNS. The third is to bring in disease iPS lines from Huntington's and Parkinson's subjects (from the respective NIH consortia and in coordination with various foundations - see letters of support. Overall) and test the specificity of signatures seen in the motor neuron diseases with other neurodegenerative conditions (both disease and response to perturbagens). All of these studies will be done in close association with the data analysis component community section (being responsive to the needs of the community). Given the speed of discovery in iPSC and new molecule generation, we also aim to be flexible in our design to allow incorporation of breakthrough technologies or drugs should they arise.
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0.946 |
2014 — 2020 |
Finkbeiner, Steven M (co-PI) [⬀] Fraenkel, Ernest (co-PI) [⬀] Rothstein, Jeffrey D (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Neuron and Glial Cellular Signatures From Normal and Diseased Ips Cells @ University of California-Irvine
DESCRIPTION (provided by applicant): There is a critical need to define the state and predict the behavior of human brain cells in health and disease. The number of different cell types in the CNS remains undefined, and despite a demographically ordained wave of neurodegenerative diseases, not a single disease-modifying therapy exists. Our knowledge of the CNS and the foundation for intervening rationally in disease would be dramatically advanced by generating quantitative molecular phenotypes essentially cell signatures of human neurons, astrocytes and oligodendrocytes from healthy people and from patients with motor neuron disease, Huntington's disease, and Parkinson's disease. The CNS is so unique that studying non-neuronal cells does not provide much assistance. Despite this desperate need, the inaccessibility of human brain cells meant studying them would have been impossible until the recent discovery of cellular reprogramming and induced pluripotent stem cell technology. Here we propose to form the NeuroLINCS consortium to accomplish these goals. We have handpicked the team to bring in critical expertise in iPSC technology, disease modeling, transcriptomics, epigenomics, metabolomics, whole genome sequencing, proteomics, high content, high throughput longitudinal single cell analysis, other cell-based assays, bioinformatics, statistics and computational biology. In addition, we are collaborating with Google to bring in special expertise in machine learning and the integration of signatures across platforms into highly predictive models of responses to perturbagens. Together, we expect to develop cell signatures of an array of human brain cell types under different conditions that should be broadly applicable to the LINCs community. We also anticipate generating innovative software tools and approaches that will make the signature generating process cheaper, faster, and more reliable. Besides the unique combination of expertise represented within NeuroLINCS, another distinguishing feature is the long track record that its members have of collaborating with each other. That collaborative spirit will be expressed in NeuroLINCS through its significant and multifaceted community outreach programs. These will involve specific and detailed plans to make the data and tools that NeuroLINCS generates available to the community, to interact with other LINCS sites, and to prepare for DCIC and the prospect of disseminating knowledge and resources at scale.
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0.946 |
2014 — 2017 |
Finkbeiner, Steven M (co-PI) [⬀] Fraenkel, Ernest (co-PI) [⬀] Rothstein, Jeffrey D (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Data Analysis & Sig - Neuron and Glial Cellular Signatures From Normal and Diseased Ips Cells @ University of California-Irvine
Data Analysis & Signature Generation Component Our goal is to generate cellular signatures of human neurons in response to perturbagens. Our studies will focus on human neurons, generated from induced pluripotent stem cells (iPSCs) (i-neurons) obtained from both healthy people and patients with neurodegenerative diseases. The cellular signature will be a composite picture of the molecular properties of a neuron that distinguish the state and determine the behavior of the cell. We will generate three classes of cellular signatures. The first will be static signatures based on quantitative molecular phenotyping involving OMIC analysis of the i-neurons. Analysis of the static signatures will highlight critical signaling pathways that distinguish a cellular response to a perturbagen. The second type of signature will be dynamic signatures generated with a novel high throughput, single cell longitudinal analysis system. Robotic Microscopy (RM). RM will be able to pinpoint critical times in the life of i-neurons as their physiology change in response to perturbagens. Analysis of dynamic signatures will guide selection of time points that will be investigated more in depth with methods that generate static signatures. In turn, elements of these static signatures will be perturbed genetically and analyzed by RM to elucidate the epistatic relationship of the components of a signature and to develop explicit multivariate predictive descriptions of cellular responses to perturbations. The third type of signature will emerge from an integration of the individual signatures using clustering methods and machine learning algorithms. The technology to analyze the data of the cellular signatures will be compatible with those produced at other sites in the LINCS network. A major innovation of our program is the implementation of novel data analysis platforms that will produce signatures that will have greater predictive value of a cell's biology than standard technologies. We will integrate Data Analysis and Data Generation, creating feedback loops to allow the cellular signatures that we generate to influence subsequent data generation. In turn, the use of machine learning algorithms in collaboration with Google will allow us to iteratively refine our signatures to make them more predictive in identifying cause and effect relationships from the cellular signatures.
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0.946 |
2014 — 2017 |
Finkbeiner, Steven M (co-PI) [⬀] Fraenkel, Ernest (co-PI) [⬀] Rothstein, Jeffrey D (co-PI) [⬀] Svendsen, Clive Niels Thompson, Leslie Michels [⬀] |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Community Interactions Outreach - Neuron and Glial Cellular Signatures From Normal and Diseased Ips Cells @ University of California-Irvine
Community Interactions & Outreach Component The NeuroLINCS Community project will plan to provide resources and tools for a broad user base of basic and clinical scientists. It has a structure to facilitate access to the various genetic and proteomic data sets, the signatures created, and the analysis tools. It is designed to be directed to researchers at the bench, clinicians developing biological disease readouts and those in computational roles. It will incorporate an assessment to demonstrate the utility of the generated resources, methodologies, and analytical tools to LINCS and non-LINCS scientific community. Importantly, it will develop and implement a plan to bring in external collaborators who may have data sets that bear on the development of cell signatures. There is an extensive plan to develop workshops, tutorials, and symposia in conjunction with the use of innovative online technologies for disseminating information to target the major LINCS goals. Finally it will develop bidirectional links with the neuroscience clinical and basic community through a series of collaborations with large National clinical data and tissue-based networks.
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0.946 |
2015 |
Svendsen, Clive Niels Targan, Stephan R. [⬀] |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
A Genetic Model of Inflammatory Bowel Disease Using Human Intestinal Organoids. @ Cedars-Sinai Medical Center
? DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) refers to a spectrum of genetic and phenotypically complex disorders that are thought to result from dysregulated immune responses to commensal microbes in genetically susceptible hosts. In IBD, the intestinal epithelium is characterized by increased permeability both in active disease and remission states, and increased permeability has been associated with elevated risk of relapse, yet the precise mechanisms remain undefined. Proteins associated with inflammation and bacteria can increase permeability, however, evidence from relatives of IBD probands suggests a genetic association as well. Progress in understanding the genetic relationship with intestinal permeability is impeded by a lack of scientific approaches to address the issue. This Ancillary R01 proposal engages the objectives of The NIDDK IBD Genetics Consortium (IBDGC) and benefits from its repository of lymphoblastoid cell lines (LCLs) generated from IBD patients and its contribution to the efforts that have identified 163 loci associated with IBD. We have developed an experimental system to approach genetic associations with intestinal permeability. Using SNPs associated with intestinal epithelium and permeability, we generated a weighted risk scoring system based on each SNP's association with IBD to selected LCLs to reprogram to form induced pluripotent stem cells (IPSCs), and to subsequently direct these IPSCs to form three-dimensional human intestinal organoids (HIOs). These HIOs contain all intestinal epithelial subtypes, possess adherens junctions and have polarized tight junctions. These HIOs will be used to study the functional relationships between SNPs and intestinal permeability. We will also use linked biospecimen tissue to assess alterations/mislocalizations of tight/adherens junctions. Lastly, patients from whom the HIOs were derived will be recalled to assess intestinal permeability - allowing us to meet a secondary objective of the NIDDK IBDGC - the rapid application of findings to patient care. The HIO system allows us to assess functional outcomes of these SNPs under defined conditions while the linked biospecimens and in vivo permeability tests allow corroboration of these outcomes in an ex vivo/in vivo setting. We hypothesize that a high risk score predisposes towards increased intestinal permeability under either basal or a subset of inflammatory conditions as compared to a low risk score and that this difference will be reproduced in a patient setting. We will approach our hypothesis through the following specific aims: 1) Determine if a high risk score is associated with alterations in the composition of HIOs; 2) Determine if a high risk score is associated with changes in the permeability of HIOs; and 3) Determine if the high risk score associated changes in tight/adherens junction composition and structure in HIOs, is reflected in small bowel tissues and in vivo permeability measurements in genotyped IBD patients. Results will establish if there is a genetic influence on intestinal permeability in IBD and delineate SNPs responsible for increased permeability.
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0.928 |
2016 — 2017 |
Bell, Caleb B. Svendsen, Clive Niels Yang, Phillip Chung-Ming |
R44Activity Code Description: To support in - depth development of R&D ideas whose feasibility has been established in Phase I and which are likely to result in commercial products or services. SBIR Phase II are considered 'Fast-Track' and do not require National Council Review. |
Tracking Cardiac Engraftment and Viability of Mipsc by Mri
? DESCRIPTION (provided by applicant): Project Summary/Abstract In order to harness the potential of cell therapies, more needs to be understood about cells post transplantation. Our goal is to experimentally validate magnetoendosymbionts (MEs) as a living MRI contrast agent to provide this insight into stem cell engraftment and viability in cardiac and neural injury model by demonstrating live cell specificity (LCS), in vivo. Bioluminescence and commercial MRI contrast agents will be used as controls for validation and to demonstrate competitive advantages. Reporter gene approaches have LCS but suffer from other complications such as need for genetic engineering that complicates regulatory developments. Existing MRI contrast agents provide full anatomic access, but lack LCS due to uptake by macrophages and nonspecific signal. Our preliminary results suggest that MEs can be used to successfully label cardiomyoctyes (iCMs) and human neural progenitor cells (hNPCs), without perturbing cell function. ME- labeled iCMs were successfully engrafted and visualized for 2 weeks in vivo (the overall goal of Phase 1). Moreover, preliminary results suggest MEs provide LCS whereas the passive MRI agent did not. In Phase 2, we propose to extend from this positive progress and fully demonstrate the value of ME- based cell tracking in a second model (hNPCs) and firmly experimentally define the LCS competitive advantage in both models. Development of imaging reagents that can effectively and specifically label cells in vivo with minimal toxicity addresses critical barrier for the cell therapies. Such a tool will lower the risk of capital investments forR&D and clinical trials, by providing the information on bio-distribution and viability needed to optimize cell therapies.
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0.903 |
2017 — 2021 |
Svendsen, Clive Niels |
UG3Activity Code Description: As part of a bi-phasic approach to funding exploratory and/or developmental research, the UG3 provides support for the first phase of the award. This activity code is used in lieu of the UH2 activity code when larger budgets and/or project periods are required to establish feasibility for the project. UH3Activity Code Description: The UH3 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the UH2 mechanism. Although only UH2 awardees are generally eligible to apply for UH3 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under UH2. |
Development of a Microphysiological Organ-On-Chip System to Model Amyotrophic @ Cedars-Sinai Medical Center
Project Abstract There are no animal models for sporadic forms of amyotrophic lateral sclerosis (ALS) and Parkinson?s disease (PD) that account for over 90% of all patients. As the genetics of these diseases are not understood there are no drug targets to go for either. This proposal aims to use MPS devices to produce some of the first sporadic ALS and PD models of disease. Using patient specific induced pluripotent stem cells from rapidly progressing patients with early onset for maximal chance of seeing phenotypes, we will differentiate the cells into motor neurons or dopamine neurons ? the two major cell types affected in the disease. Using cutting edge electrophysiology techniques and metabalomics combined with RNAseq and proteomic analysis we will establish solid biomarkers that define these two diseases when compared to healthy controls (UG3 phase). We will then develop novel MPS screens using the NCATS library of compounds based on the biomarkers discovered in the UH3 phase (UG3 phase). Together these studies will produce some of the first models of sporadic neurological disease using iPSC technology combined with MPS technology. Cedars-Sinai and the company Emulate have a 2 year relationship that forms the foundation of this proposal and an integrated institutional platform on which to collaborate to achieve the goals of the study.
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0.928 |
2020 — 2021 |
Baloh, Robert Svendsen, Clive Niels |
UG3Activity Code Description: As part of a bi-phasic approach to funding exploratory and/or developmental research, the UG3 provides support for the first phase of the award. This activity code is used in lieu of the UH2 activity code when larger budgets and/or project periods are required to establish feasibility for the project. |
A Microphysiologic Multicellular Organ-On-Chip to Inform Clinical Trials in Ftd/Als @ Cedars-Sinai Medical Center
Project Summary/Abstract Frontotemporal dementia (FTD) is a common dementia syndrome in patients under age 65, while amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons causing death from respiratory failure within 3-5 years. FTD and ALS represent a spectrum of neurodegeneration, with significant overlap clinically, pathologically, and genetically. Aggregates of TDP-43 are the defining pathology of FTD (FTLD-TDP variant) and ALS, and the most common genetic cause of both FTD and ALS are repeat expansions in the C9orf72 gene. C9orf72 is expressed in multiple cell types in the brain including in microglia and neurons, and there is strong evidence that interaction between different cell types are necessary for pathogenesis of FTD/ALS. We will develop a microphysiologic system (MPS) using human induced pluripotent stem cell (iPSC) derived cortical neurons, astrocytes and microglia on a 3D platform that includes a blood brain barrier (BBB) component to model C9-FTD/ALS forebrain on a chip. Our goal in this project is to develop a highly reproducible and translatable in vitro human cell-based model of FTD/ALS to discover and validate translatable biomarkers for preclinical efficacy testing, and to assist in patient stratification for clinical trial design. We propose to i) develop and validate robustness of a 3D forebrain MPS incorporating cortical neurons and astrocytes, microglia and brain microvascular endothelial cells (BMECs) derived from human iPSCs; ii) utilize FTD and ALS patient derived forebrain MPS's to identify disease biomarkers in C9orf72 related FTD/ALS; iii) cross validate biomarkers identified using clinical data and pathology from C9-FTD/ALS patients used to seed the chips, and iv) assess and stratify responses of C9-FTD/ALS fMPS models to five different therapeutics entering early phase clinical trials ranging from antisense oligonucleotides to small molecule modulators of mitochondrial function, endocytic trafficking and cell death pathways.
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0.928 |
2020 |
Svendsen, Clive Niels |
UG3Activity Code Description: As part of a bi-phasic approach to funding exploratory and/or developmental research, the UG3 provides support for the first phase of the award. This activity code is used in lieu of the UH2 activity code when larger budgets and/or project periods are required to establish feasibility for the project. |
A Lung-Chip Microphysiological System to Model Sars-Cov-2 Infection and Test Novel Therapeutics @ Cedars-Sinai Medical Center
Project Abstract SARS-CoV-2 novel coronavirus has caused a pandemic, presenting us with an urgent need to develop new models to study the pathophysiology of infection and test innovative therapeutics to combat disease. This proposal aims to use chip-based microphysiological systems to establish a model of the human lung to investigate SARS-CoV-2 infection and test novel antisense oligonucleotide (ASO) therapies to reduce viral entry and replication. Using human primary and induced pluripotent stem cell (iPSC)-derived lung epithelium, we will generate both proximal and distal airway chip models, infect with live SARS-CoV-2, and test newly designed ASOs to target host cell components to prevent viral entry and conserved viral sequences to prevent replication. We have assembled an expert team of lung biologists, virologists, and pharmaceutical industry partners to complement the iPSC and organ-chip technologies our lab has been developing over the past five years. We feel that the approach presented in this proposal will yield rapid results by generating human- relevant models to better understand the pathological mechanisms of SARS-CoV-2 infection and test novel therapeutic strategies currently in development by our pharmaceutical industry partner.
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0.928 |