1998 — 2002 |
Scadden, David T |
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. |
Kaposi's Sarcoma Herpesvirus as Target For Immunotherapy in Multiple Myeloma @ Dana-Farber Cancer Institute
The recently identified gamma herpesvirus, Kaposi's sarcoma herpesvirus or KSHV, has been associated with multiple neoplasms including Kaposi's sarcoma, non-Hodgkin's lymphoma, Castleman's disease and multiple myeloma. The role of KSHV in transformation is not clear, but clinical data strongly support the role of immunologic competence in controlling KSHV- related disease in transplant or AIDS-related KS. Therefore, characterization of the cellular immune response to KSHV may provide the basis for immunologic interventions to treat and prevent KSHV-related cancer. The identification of KSHV may provide the basis for immunologic interventions to treat and prevent KSHV-related cancer. The identification of KSHV in multiple myeloma bone marrow stromal cells, but not in MGUS or other disorders has provided a highly exploitable target for immune based therapies. The hypothesis that KSHV is linked top multiple myeloma will be analyzed in detail focusing on the characterization of the immune response to KSHV in myeloma to generate specific immunologic strategies to treat and/or prevent this disease. Specifically, we propose. 1. To further define and characterize KSHV in multiple myeloma. 2. To assess CTL response to KSHV in myeloma and the prodromal condition, MGUS. 3. To assess KSHV-specific CD4 helper cell responses in myeloma and MGUS.
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0.909 |
2000 — 2002 |
Scadden, David T |
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. |
T Cell Neogenesis After Stem Cell Transplantation @ Dana-Farber Cancer Institute
Reconstitution of T cell immunity following bone marrow transplantation is critical for the protection of the host from both infectious pathogens and tumor recurrence but this process is slow and is limited by parameters which are poorly defined. Further characterization of the mechanisms limiting immune reconstitution is restricted by available experimental systems. To address this issue, we have developed a novel model of in vitro T lymphopoiesis that recapitulates the differentiation of functional T cell from lineage negative bone marrow progenitor cells. In this project we propose to use this model system to examine T lymphopoiesis after allogeneic stem cell transplantation and to develop therapeutic strategies based on ex vivo T cell generation. We propose to adapt the in vitro system to provide a semi-quantitative measure of total and subset specific lymphopoietic output and repertoire complexity from input stem cells. We will test samples derived from patients undergoing transplantation and correlate in vitro findings with clinical parameters of immune reconstitution and T cell generation. These studies will determine whether stem cell lymphopoietic capacity dictates immune reconstitution and may provide a method by which the immunologic potential of a stem cell graft may be defined prior to transplantation. In addition, we will assess the capability of the in vitro system to provide T cell neogenesis and determine if reactivity to defined antigens can be achieved. Determination of whether negative selection permits expansion of a fully tolerized T cell population may enable adoptive transfer for host defense. Specific Aims: 1. To optimize an in vitro model system that supports the differentiation of human hematopoietic stem cells into functional polyclonal T cells. 2. To establish methods for positive and negative selection of donor T cells in vitro. 3. To develop in vitro correlates of in vivo T cell lymphopoiesis. 4, To develop methods for in vitro expansion of mature polyclonal na ve T cells for adoptive T cell infusion after allogeneic BMT.
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0.909 |
2008 — 2012 |
Scadden, David T |
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. |
Harvard Stem Cell Institute Training Program For Pre- and Post-Doctoral Fellows
[unreadable] Description (provided by applicant): As our understanding of stem cell biology is rapidly advancing, the application of this knowledge toward the development of novel therapeutic strategies becomes increasingly imminent. Successful translation of the basic science into clinical applications requires a novel type of scientist who has been trained across the medical-science spectrum. This calls for an educational program that integrates a strong knowledge base in stem cell research with experience in the clinical application of these new technologies. Such a program will ensure that participants can establish successful independent research programs to advance the development and application of stem cell based therapies. Our current proposal aims at establishing a Stem Cell Training Program at the Harvard Stem Cell Institute (HSCI) to prepare pre- and post-doctoral students for a career in stem cell biology. This program will provide outstanding basic and clinical stem cell biology research based on multi-disciplinary, disease-directed research and patient care, with an emphasis of translating new discoveries and understandings in stem cell science into clinical therapeutics for degenerative diseases. An essential component of the program is group mentorship, which will guide trainees to become independent scientists and help shape their future careers. Trainees in this program will work independently on their own research, while as a group will address key areas of stem cell research including: identification and characterization of stem cells; differentiation and functionality of these cells; alternative methods to derive stem cells; generation of patient-specific cell types; generation of tools for cellular therapy; and application of stem cells in therapy and drug discovery. In addition, they will complement their practical experience with participation in classes, seminars and symposia, which will enhance their awareness and consideration of not only of the science, but of the ethical, political, and social implications of their work. The HSCI Training Program will provide three pre-doctoral and four post-doctoral trainees with a collaborative platform to study many aspects of stem cell biology. Although located at different institutions and under the mentorship of different Principal Investigators, this program will shape the direction of their scientific research and career paths. Sharing of data, core facilities, and face-to-face interactions are essential to the success of this program and will be facilitated through HSCI's inter-disciplinary educational and scientific strategy. [unreadable] [unreadable] [unreadable]
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1 |
2009 — 2012 |
Scadden, David T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Stem Cell Engagement of the Niche
DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the molecular interactions between hematopoietic stem/progenitor cells (HSPC) and their microenvironment using two distinct in vivo model systems. One is murine and disease focused. The other is zebrafish and focused on the normal. Both will employ high resolution imaging. The murine system takes advantage of a unique finding that modifying a single gene associated with RNA processing (Dicer1) in a single subset of mesenchymal cells can dramatically alter hematopoiesis, creating a complex syndrome resembling human myelodysplasia. Defining the basis for the alteration in HSPC function will reveal molecular regulators at the niche-HSPC interface that we propose to then test in the zebrafish system, developing methods to enhance the use of that model in studies of the niche. In parallel, moderate through-put screening technology has been developed for the zebrafish that will be used to identify modifiers of HSPC engraftment of the niche. These will then be further assessed in murine systems establishing convergence or divergence of the two models. The two approaches will be conducted concurrently with data exchange between them enabling testing of information from each system in the other. Through this interactive exchange of two distinct systems, we anticipate a rapid identification and verification of mediators and potential chemical perturbogens of hematopoietic-microenvironment interactions that can then be considered for clinical application. Our aims are to: 1. Define the molecular basis for complex dysfunctional hematopoiesis with osteoprogenitor specific deletion of Dicer1 in the mouse. 2. Identify modifiers of HSPC-niche interactions in the zebrafish. 3. Determine the correspondence between zebrafish and mouse hematopoietic stem cell interactions with the niche Successful accomplishment of these aims will yield insight into normal and dysfunctional stem cell interactions with the niche and provide potential means of altering them. Further, it will define the ability to combine the strengths of the mouse to model disease with the strengths of the zebrafish to conduct broad screens as a means of accelerating discovery in hematopoiesis research. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to define the basis for a mouse model of the human blood disease, myelodysplasia and to identify compounds that might positively affect the bone marrow. We will use a unique combination of mouse and zebrafish model systems examined by molecular, chemical and imaging techniques.
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1 |
2011 — 2014 |
Mooney, David J [⬀] Scadden, David T Weitz, David A (co-PI) [⬀] Westervelt, Robert M (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Building the Hematopoietic Stem Cell Niche
DESCRIPTION (provided by applicant): A hierarchal and tightly controlled organization of various cell types is the hallmark of normal tissues and organs, and the hypothesis underlying this proposal is that pre-defining the specific location and resultant cell- cell interactions of individual cells within a 3D tissue construct will allow one to create highly functional tissues in which the role of cell-cell interactions on cell phenotype can be precisely delineated. This concept will be explored by developing a 3D model of human hematopoiesis, in which osteoprogenitors and vascular cells will be probed for their roles in defining the hematopoietic stem cell (HSC) niche. The specific aims include (1) the development of microfluidic techniques to allow large-scale encapsulation of single cells in highly defined extracellular matrix mimics in order to determine how matrix cues regulate mesenchymal stem cell differentiation at the single cell level, (2) the creation of hybrid integrated circuit/microfluidic circuit systems to enable one to assemble picoliter drops containing individual cells and synthetic ECM into 3D assemblies with pre-defined structure and organization, and (3) determining whether appropriate in vitro assembly of HSCs and cells representative of the bone marrow HSC niche can yield functional hematopoietic tissues capable of recreating hematopoiesis in vitro. Success in this project will lead to the creation of a new set of tools that will enable formation of 3D tissues with precisely defined cell placement, and homotypic and heterotypic cell-cell interactions. These tools are likely to be broadly useful to the creation of new in vitro models of tissue development and drug screening, and in vivo tissue replacements from a variety of cell types. As stem cells are particularly sensitive to environmental cues, inappropriate cell-cell and cell-matrix interactions likely lead to the irreversible and undesirable alterations in stem cell differentiation fate found in culture. The systems developed in this project will allow us to investigate the specific role of vascular cells and osteoprogenitors/osteoblasts in maintaining the human HSC niche, which is a difficult question to address in vivo. It is crucial to better define and create models of the niche to understand normal hematopoiesis and pathologies involving blood cells, and to enable hematopoiesis on demand in various therapeutic venues. The key studies to date on this topic have relied on rodent models, and the relevance of many findings to human biology is currently unclear. (End of Reviewers' Comment)
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1 |
2011 — 2015 |
Kalluri, Raghu [⬀] Scadden, David T |
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. |
Stromal Regulation of Bone Metastasis @ University of Tx Md Anderson Can Ctr
DESCRIPTION (provided by applicant): Cancer accounts for 8-9 million deaths a year, 80% of which are due to systemic spread of cancer to distant organs. It has long been recognized that primary cancers spread to distant organs with 'specific' preference, and skeleton/bone is one of the most common organs to be affected by metastatic cancer. Among primary cancers, prostate cancer is considered to be an orthotropic tumor with specific predilection to form bone metastasis. Over 70% of prostate cancer patients exhibit bone metastasis as detected during the disease course or autopsies. Prostate cancers are amongst the most commonly diagnosed malignancies and the 2nd leading cause of cancer death in men. Bone metastases are the predominant reason for prostate cancer related deaths, and current therapies have very short-term benefits, if any. To achieve the central objective, the laboratories of Kalluri, Pandolfi and Scadden have joined forces to propose a focused and cohesive plan to study the biology of bone metastasis. The three projects in this TMEN network will generate new genetic mouse models of metastatic prostate cancer, offer new insights into the biology of prostate cancer initiating cells, identify possible bone metastasis cell of origin, establish the role of tumor microenvironment in metastatic prostate cancer with specific emphasis on prostate and bone microenvironment, identify new therapeutic targets against metastatic prostate cancer and evaluate a new drugs for metastatic prostate cancer in pre-clinical trials. Successful completion of this proposed network proposal will offer significant new advances in area of metastatic prostate cancer.
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0.957 |
2012 — 2015 |
Scadden, David T |
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. |
Bone Microenvironment Contributions to Metastatic Disease @ University of Tx Md Anderson Can Ctr
Project Summary: Metastasis is a multi-step process that involves multiple different tissue components supporting a heterotopic cancer cell. We propose that mesenchymal cell interactions with cancer cells play a critical role in the successful engraftment of the cancer in a metastatic site. We will test that hypothesis through the examination and manipulafion of specific subsets of mesenchymal cells interacting with primary prostate cancer cells of defined genotype. PHS
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0.957 |
2015 — 2020 |
Scadden, David T |
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. |
Project 1: Clonal Dynamics Guiding Curative Therapies For Acute Myeloid Leukemia @ Dana-Farber Cancer Inst
Project Summary / Abstract Acute myeloid leukemia (AML) is rapidly fatal, poorly controlled disease that can be rapidly brought into complete remission but where relapse kills the vast majority of patients. The genetic evolution of the disease has been defined retrospectively, but the basis for resistance to therapy and effective strategies to overcome it are lacking. This project seeks to take advantage of well-defined mouse models where a human leukemogenic allele induces highly penetrant, lethal AML that can be temporarily brought into remission by chemotherapy agents used in patients. Combining these basic biologic features with novel strategies for quantitatively assessing clonal behavior, clonal molecular features, physical localization and the in vivo parameters of growth pathway, cell cycle and apoptosis over time will provide multidimensional datasets for mathematical modeling of the parameters correlating with: 1. Clonal dominance in vivo (Specific Aim 1) and, 2. Sensitivity/resistance to chemotherapy in vivo (Specific Aim 2). The models will guide experimental testing of the role of the parameters in the in vivo behavior of the disease that will then be used to develop and test methods for enhancing durable control of AML (Specific Aim 3).
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0.909 |
2015 — 2019 |
Scadden, David T |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
A Defend and Destroy Approach to Curing Hiv
? DESCRIPTION (provided by applicant): This proposal seeks to achieve a durable cure of HIV through the use of autologous gene-modified cells in a 'Defend and Destroy' approach. Our central premise is that autologous cells can be used to eradicate HIV if they are 1. Genetically rendered HIV-uninfectable, and, 2. Enhanced in their activity by specific measures to destroy viral reservoirs. We have therefore assembled a team of investigators with complementary areas of expertise to execute the following specific aims: Specific aim 1: Utilize novel genetic modification technologies to engineer HIV- resistant immune systems with enhanced ability to destroy viral reservoirs. (Derrick Rossi, PI) This takes advantage of expertise in the Rossi lab with the CRISPR- Cas9 genome editing system and modified-mRNA technology. Specific aim 2: Enhance engraftment of gene modified hematopoietic stem cells with reduced toxicity, niche sparing conditioning of the host to minimize morbidity and costs without compromising targeting of viral reservoirs. (David Scadden, PI) Specific aim 3: Test approaches for viral control and vira reservoir depletion in a HIV-infected and anti-viral treated 'humanized' mouse model. (Todd Allen, PI) Specific aim 4: Pre-clinical development of HIV-resistant hematopoietic stem cells. (CRISPR Therapeutics, Rodger Novak, PI) Each aims maps to a project and the projects are supported by two cores: A. Administration and Biostatistics, and, B. Humanized mouse core generating, treating and analyzing BLT mice infected with HIV and treated with triple drug anti-retroviral therapy. Each of the four Specific Aims described above could be conducted independently as a scientifically significant research project. However, it is the synergy achieved through the coordinated accomplishment of these aims that will enable the testing of a multi-pronged strategy for eradicating HIV infection. Testing of such a complex set of strategies, which together represent the platform for a Defend and Destroy approach to curing HIV infection, would simply not be possible if any one project were conducted out of the context of the other three. Thus, it is only the concerted execution of this package of four Projects, supported by two critical Cores, that will facilitate testing of the proposed, highly novel strateg for curing HIV.
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1 |
2015 — 2018 |
Scadden, David T |
R24Activity Code Description: Undocumented code - click on the grant title for more information. |
Cell and Molecular Dynamics of Hematopoiesis in Vivo
? DESCRIPTION (provided by applicant): This proposal seeks to create a unique biomolecular dataset for the hematopoiesis research community by defining the molecular basis for functional heterogeneity among hematopoietic stem and progenitor cells (HSPC) in vivo in the mouse. This will be accomplished at a clonal level, sequentially using an engineered mouse strain that permits clonal tracking, cell isolation and molecular analyses. The bone marrow microenvironment will be analyzed under similar conditions of regions in physical proximity to hematopoietic stem and progenitor cells. Combined this dataset will provide a comprehensive molecular characterization of highly annotated in vivo cell behaviors under unperturbed and stress conditions. It involves three investigators with distinctive and complementary areas of expertise in the field of hematopoiesis, biomolecular computation and high resolution in vivo imaging. It involves distinctive tools generated by the interaction between these investigators and these disciplines. Successful accomplishment of this proposal will result in a unique resource coupling molecular data with functional attributes of individual clones of blood forming cells. It will be useful for the field and guide future studies by others to determine the molecula drivers of specific functions of stem and progenitor cells.
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1 |
2015 — 2019 |
Scadden, David T |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Improving Stem Cell Transplant Safety and Efficacy to Cure Hiv-1 Infection
Abstract The potential for hematopoietic stem cell therapy to cure HIV disease gains credence from the experience of the `Berlin patient' and is made more feasible by emerging developments in gene editing, particularly when coupled with non-mutating RNA based transduction strategies: the strength of Project 1. It is also now possible to credibly test anti-HIV cell therapies pre-clinically using humanized mouse models: the strength of Project 3 and Core B. What remains a challenge to reduce the complexity of hematopoietic stem cell transplant so that it may be more readily adopted in settings that are not acutely life threatening such as chronic HIV disease. Gene editing will make possible autologous cell transplant thereby removing the devastating complication of graft versus host disease. However, `conditioning' to enable stem cells to engraft the marrow is toxic and requires resource intensive hospitalization as currently practiced. We propose to use methods of modifying hematopoietic stem/progenitor cells' (HSPC) interactions with their bone marrow microenvironment to test novel, niche sparing methods to enable HSPC engraftment with reduced toxicity and potentially less cost, while assessing the impact on HIV-1 reservoirs and generation of T lymphoid reconstitution. The specific aims of this project are: Specific aim 1. Competitively advantage donor cells over endogenous stem cells through selective inhibition of eicosanoid signaling. Specific aim 2. Enhance niche vacancy without niche toxicity through manipulation of CXCR2 and heparan sulfate proteoglycan interactions between stem cells and the bone marrow niche. Specific aim 3. Selectively deplete endogenous hematopoietic cells using a novel saporin-antibody hybrid based targeting system. Specific aim 4. Test the role of conditioning in reducing the `reservoir' of HIV infected cells by comparative analysis of cytotoxic and non-cytotoxic methods of conditioning in HIV infected xenogeneic models. Test methods of enhancing T cell reconstitution to improve generation of anti-HIV-1 immunity. If successful, this project will provide specific interventions that can lower the barrier for gene edited HSPC transplantation as an approach to cure HIV/AIDS.
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1 |
2015 — 2019 |
Scadden, David T |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Core a: Administrative and Biostatisitcs Core
Abstract: The Administrative Core will be responsible for the management, coordination and supervision of the overall project. It includes scientific, administrative and biostatistical expertise for the projects and leverages existing resources at the participating institutions. The Core will organize continuation of the ongoing regular meetings of the participants and facilitate communication by electronic and in-person means. It will track progress of each project and the overall project toward agreed upon milestones and provide a forum for data analysis, publication decisions and responses to input from the U19 Scientific Advisory Panel. It will provide overall fiscal oversight, be responsible for assuring compliance with NIH reporting requirement and facilitate conflict resolution. It will also provide a common biostatistical source for the design and analysis of experiments and integrate data on xenotransplantation and HIV control with an existing common database at the Ragon Institute. It will be responsible for travel to the U19 coordinating meetings and will facilitate interactions between academic and commercial participants particularly with regards intellectual property. It will be explicitly attentive to inclusion and creating a culture of collaborative attention to the larger goal of curing HIV disease. It will be supportive of junior members of the investigative team and provide mentoring relationships for trainees. The specific aims of the Core are to: Aim 1: create a team with common purpose dedicating to curing HIV through an open, communicative and collaborative culture Aim 2: foster entreprenurial activities to enhance the ability of discoveries in the project to become real world applications Aim 3: manage the overall project by tracking the progress of individual projects, assuring accountability to agreed upon milestone and supervising the exchange of information, data analysis and publication decisions Aim 4: provide biostatistical support for all projects and Core B Aim 5: assure financial and reporting compliance with NIH standards
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1 |
2017 — 2019 |
Mooney, David J [⬀] Scadden, David T Weitz, David A (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Msc Encapsulation With Thin Gel Coating
Mesenchymal stem cell (MSC) therapies are currently in widespread clinical testing for a number of diseases, but a common theme of trials to date is the massive loss of the MSCs following transplantation. This outcome likely relates to the approach utilized for delivery ? clinical trials typically utilize intravenous (iv) infusion of suspended cells. In contrast, encapsulation of cells in various materials has been widely explored in preclinical studies to enhance transplanted cell survival, but the resulting particles and devices have been too large to allow iv infusion, providing a significant practical obstacle to their clinical implementation. Further, as the bioactivity of MSCs is now widely ascribed to paracrine secretions, control over the secretome of the cells following transplantation may be crucial to their clinical success. We recently developed a highly efficient microfluidic process to encapsulate single cells in a very thin layer of hydrogel (~ 5 microns); this thin coating still allows cells to be infused intravenously, but dramatically increases both their survival and the duration of their secreted products in the bloodstream. We hypothesize this technology will provide a timely new tool for MSC therapies and dramatically expand their clinical utility. Here, we propose to further develop this new technology, and to study its utility in context of hematopoietic stem cell therapy (HSCT). We have put together a unique team to address the hypothesis underlying this project, with leaders in microfluidics technology (Weitz), biomaterials (Mooney), and hematopoietic stem cell (HSC) biology and HSCT (Scadden). We will pursue our objectives by: (1) Tune the chemical and physical properties of microgels, and scale-up the microfluidics technology to enable clinically relevant numbers of MSCs to be encapsulated with high efficiency, (2) Determine how MSC persistence and paracrine secretions following transplantation can be tuned, both qualitatively and quantitatively, by the chemical and physical properties of the encapsulating alginate hydrogel, and (3) Study the impact of gel-encapsulated MSCs, following intravenous infusion, on the treatment of graft versus host disease (GVHD) following HSCT in a rodent model. At the completion of these studies we will have validated the effectiveness and practicality of this approach to MSC therapy. Importantly, the results of these studies will help to define how the MSC secretome impacts the effectiveness of MSCs in GVHD, and the importance of immunoprotection of the MSCs following transplantation. Further, this approach is also likely to be broadly useful to the wide array of other clinical applications of MSCs and to the use of many other types of stem cells.
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1 |
2020 — 2021 |
Scadden, David T |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Enhancing Regeneration of Stem Cell-Derived Hiv-Specific Immune Effectors @ University of Southern California
Project Summary In the previous U19 award, we developed a non-genotoxic antibody based method of conditioning animal recipients for hematopoietic stem/progenitor cell (HSPC) transplantation. This approach is now being developed for human use and non-human primate testing by Magenta Therapeutics, the commercial participant in this proposal. We also developed a method of enhancing T cell neogenesis post-transplantation that takes advantage of prior work defining the bone marrow niche for T-competent progenitors, creating an easy to administer, off the shelf bone marrow cryogel. Subcutaneous injection of the cryogel leads to improved T competent common lymphoid progenitor (CLP) production, increased thymocytes, TREC+ cells, mature T cells, expanded TCR repertoire and improved immune function in mouse models. Here, we will combine it with the gene modification technology of the Cannon and Kiem labs and the antibody-drug conjugate technology of Magenta to determine whether we can increase the regeneration of a functionally complex, HIV protected adaptive immune system to protect against acute HIV infection, control viremia in infected hosts and potentially, reduce the tissue reservoir of infected cells. The strengths of the Scadden lab in hematopoiesis and transplant and the Allen lab in HIV infection and immunity will complement each other in testing this approach in humanized mice. We will closely interact with the Cannnon and Kiem labs on gene modifying approaches to engineer anti-HIV HSPC and extend testing to the non-human primate. Collectively, these efforts will provide immediate pre-clinical testing a of a strategy to cure HIV through low-toxicity approaches to rebuild an infected individual?s immune system.
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0.957 |