1998 — 2001 |
Keene, Christopher D |
F30Activity Code Description: Individual fellowships for predoctoral training which leads to the combined M.D./Ph.D. degrees. |
Transplantation of Fetal Lge in Huntingtons Models @ University of Minnesota Twin Cities
Abstract: DESCRIPTION (Adapted from applicant's abstract): The ultimate objective of the proposed research is to provide clinicians with data and techniques requisite for the implementation of transplantation of neural tissue in the treatment of Huntington's Disease (HD). Specific Aim 1 will address whether transplanted cells can ameliorate the cognitive deficits associated with HD. We will assess this using delayed alternation and spatial learning and memory tests pre- and post-transplantation in a rat model of HD. These measures will be correlated with graft growth, survival, and the neurochemical phenotype of the grafts to identify graft characteristics which are important for recovery of cognitive function. Transplant efficacy must be assessed in an animal model evolutionarily more closely related to humans in order to test more complex behavioral measures and to evaluate the clinical applicability of the procedure. Specific Aim 2 addresses these issues in a non-human primate model of HD. Cells will be transplanted into rhesus monkeys with 3-nitropropionic acid lesions of the caudate and putamen. Monkeys will be tested behaviorally pre- and post-transplantation by videotape assessment of incidence of choreiform movements, orofacial dyskinesia, dystonia, and manual dexterity. Further tests will be conducted to assess cognitive effects, including passive avoidance and visual discrimination tasks. At the end of the behavioral testing the animals will be sacrificed and their brains removed for histological processing. Growth and survival of the graft, as well as its cellular phenotype, will be correlated with behavioral data to evaluate graft efficacy and potential for clinical application. Clinically, one of the most important weaknesses of cell transplantation procedures is the absence of a reliable method for monitoring graft development. In Specific Aim 3, tissue grafts in rats and monkeys with excitotoxic striatal lesions will be monitored using 1-H nuclear magnetic resonance spectroscopy (NMRS) which utilizes MEGA, a frequency selective refocusing technique, to monitor GABA levels in vivo. In simultaneous experiments, rats with intrastriatal lesions and grafts will be monitored using NMRS. The striata of rats will be imaged/measured using the 9.4 Tesla magnet pre- and post-lesioning. Volumetric, morphologic and immunohistochemical measures will be taken periodically and correlated with the values obtained from the imaging studies and with behavioral measures from each rat.. The imaging data will be correlated with the final histological and behavioral measures obtained from the primate subjects at the end of the experiments to evaluate the clinical efficacy and applicability of this NRMS technique in tissue transplantation.
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0.945 |
2010 — 2014 |
Keene, Christopher Dirk |
P50Activity 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 grants differ from program project grants 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. |
Modulation of Abeta Peptide Accumulation and Neuron Damage in Vivo With Adult Bon @ University of Washington
Abbreviations; Address; Adult; Allogenic; Alzheimer's Disease; Amyloid; Amyloid beta-Protein; amyloid peptide; Area; Autologous; base; Bone Marrow; Bone Marrow Transplantation; Brain; Cell Transplants; cell type; Cells; Cerebrum; Chronic Disease; Clinical; clinical application; clinically relevant; Complement; cytokine; Data; Deposition; Disease; effective therapy; Engraftment; Exclusion; Foundations; Funding; Future; gene therapy; Genetic; genetic manipulation; Genetically Engineered Mouse; Hematopoietic stem cells; Hippocampus (Brain); Human; Immune response; Immunologics; immunoregulation; in vivo; Individual; Knowledge; Life; Lupus; Malignant Neoplasms; Marrow; Measures; Mediating; Medical; Methods; Microglia; Modality; mouse model; Multiple Sclerosis; Mus; Neurodegenerative Disorders; Neurons; neuroprotection; neurotoxic; neurotoxicity; Neurotoxins; Non-Malignant; novel; novel therapeutic intervention; novel therapeutics; older patient; paracrine; Pathway interactions; peptide B; Peptide Metabolism; Peptides; Peripheral; Phagocytosis; preconditioning; Procedures; Prostaglandin E Receptor; Prostaglandins; Prostaglandins E; Protocols documentation; Radiation; Reaction; receptor; research study; Resources; response; Rheumatoid Arthritis; Safety; Senile Plaques; Technology; Testing; Therapeutic; Toxic effect; Transgenic Mice; Transplantation; Treatment Efficacy; United States National Institutes of Health; virtual; Work
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1 |
2015 — 2019 |
Keene, Christopher Dirk |
P50Activity 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 grants differ from program project grants 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. |
Neuropathology & Targeted Molecular Testing Core @ University of Washington
CORE D: NPTMT ABSTRACT The Neuropathology and Targeted Molecular Testing (NPTMT) Core has been a valuable and frequently utilized resource for UW ADRC as it pursues its vision of precision medicine for Alzheimer's disease (AD) as well as for local and national AD research. The mission and thus, specific aims, have not significantly changed from the current award: (i) provide diagnostic expertise, (ii) provide targeted biomarker and genetic testing, (iii) build a highly accessible repository of brain tissue and fluid, (iv) develop innovative approaches, and (v) maintain a rich training environment. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy individuals and those in the early stages of AD while ensuring proper safeguards.
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1 |
2020 — 2021 |
Close, Jennie Leigh (co-PI) [⬀] Hawrylycz, Michael Hodge, Rebecca Dawn Keene, Christopher Dirk Lein, Ed |
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 Platform For Cell Type-Level Transcriptomic, Epigenomic and Spatial Interrogation of Alzheimer's Disease
ABSTRACT (OVERALL) Our understanding of the neuropathology in Alzheimer?s disease is crude and largely centered on characteristic deposition of a few pathological proteins. Catalyzed by the BRAIN Initiative, a new generation of molecular tools to characterize the transcriptome, epigenome and spatial organization of single cells in complex brain tissues is rapidly revolutionizing our understanding of the diversity of cell types and their selective genetic profiles. These tools are applicable to postmortem human brain tissues and promise to expand our understanding of the core cellular and molecular correlates and mechanisms underlying Alzheimer?s disease. The goal of the proposed Center is to bring together experts in Alzheimer?s disease research and large-scale molecular/anatomical brain mapping to modernize Alzheimer?s disease tissue banking methods, and to combine traditional and quantitative neuropathology with emerging single nucleus transcriptomics, single nucleus epigenomics and spatial transcriptomics technologies. Applied to clinically typical Alzheimer?s cases of varying severity in an iterative and adaptive design, these techniques are expected to identify increasingly refined molecular pathways associated with specific neuronal and non-neuronal cell types and yield valuable insights into cell-type selective vulnerability or resistance to pathology. This increased resolution of AD pathology in terms of cell types and molecular pathways should provide mechanistic insights and hypotheses on disease initiation and progression, which we aim to use to catalyze the AD research community through the creation of an open access data resource linked with other large-scale brain mapping efforts. This Center framework is designed to be extensible to additional data modalities and technological advances as well as broader cohorts representing Alzheimer?s disease subtypes and Alzheimer?s disease related disorders in the future.
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0.907 |
2020 — 2021 |
Keene, Christopher Dirk |
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. |
Novel Platform For Research Brain Banking and Characterization Using Integrated Traditional and Quantitative Analyses to Promote Precision Neuropathology of Alzheimer's Disease
ABSTRACT (PROJECT 1) The underlying goal of Project 1 is to facilitate an integrated neuropathological approach incorporating traditional and quantitative pathology techniques with cell-type and molecular profiling to develop a unique resource to promote next generation AD research. It leverages existing collaborative relationships between UW Neuropathology and the UW ADRC and Kaiser Adult Changes in Thought studies for research autopsies. Project 1 will implement newly developed protocols for modernized autopsy sampling and preservation of brain tissue that are amenable to state-of-the-art cell type and molecular profiling techniques (Aim 1), as planned in Projects 2 and 3. Deceased subjects from both studies with short post-mortem intervals will enter Project 1 tissue pipeline to ensure high quality tissue preservation and availability for -omics Projects, with appropriate quality control measures at each step. Each ACT and ADRC autopsy includes qualitative neuropathological examination with extensive sampling and a battery of immunostains specific to pathologic peptides according to the latest guidelines. Neuropathological data from each case will be reviewed at regular meetings with Project 1 investigators; cases along the spectrum of AD pathology, but lacking co-morbid neuropathologies, will be promoted to eligibility for inclusion in Aim 2 and the Projects 2 and 3 pipelines. Aim 2 expands analysis of selected cases to include all regions of interest for Projects 2 and 3, but also regions of relevance to current AD cognitive subtypes and biomarker studies with a battery of immunohistochemical stains, image analysis, and quantitative assays to characterize neurodegeneration (pathologic peptides), neurotoxicity (neurons, synaptic markers, stains for white matter and oxidative stress), and reactivity (astrocytes, microglia, inflammation). In Aim 3, results from cell-type and molecular profiling studies in Projects 2 and 3 will be prioritized for targets identified in early AD pathogenesis, validated, and extended to the broader autopsy cohort to determine relevance. Quantitative measures for these analyses may include Luminex-based immunoassays and other techniques proteins and metabolites of neurodegeneration, neurotoxicity, and neuroinflammation/gliosis in regions and subjects of interest. We predict, based on the last five years, approximately 30 cases per year that are eligible for inclusion in Aim 2 and Project 2 and 3 pipelines. Each brain that goes through Project 1 pipeline, even if not selected for inclusion in the -omics components of the Center, will be preserved according to these novel protocols and deeply characterized for future studies of AD subtypes, risk variants, related disorders, and exposure profiles.
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0.907 |
2020 — 2021 |
Keene, Christopher Dirk |
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. |
Precision Neuropathology Core @ University of Washington
Abstract - Precision Neuropathology Core The Precision Neuropathology (NP) Core has been a valuable and frequently utilized resource for UW ADRC in support of its vision of characterizing and understanding heterogeneity of Alzheimer's disease and related dementias (ADRD). The NP Core has fostered development of innovative approaches to assess neuropathology of ADRD, which are essential to more precisely measure neuropathologic change. We build on this tradition of innovation in this proposal by applying novel, highly quantitative multiplexed immunoassays developed in the NP Core to measure neuropathology that, combined with better methods of collecting and storing tissue for state-of-the-art applications including single cell molecular profiling, expanded pathological sampling informed by structural and functional imaging, ex vivo MRI-guided pathologic sampling in every brain, and 3D image reconstruction, and quantitative analysis in both gross and microscopic samples, enable us to deeply characterize the structural substrate for ADRD heterogeneity. We combine this comprehensive analysis of human brains with a cell types and stem cell component composed of experts in their respective fields who are committed to providing support for ADRD-related mechanistic studies, all while supporting every core of the ADRC and local and national research. Thus, our Aims reflect our commitment to integrate traditional diagnostic excellence and extensive tissue and data sharing with radiographically informed extensive sampling and a battery of highly quantitative, molecularly specific tissue and in silico approaches to precisely measure ADRD neuropathology. Our specific aims are to (i) build a highly accessible repository of brain tissue and fluid, (ii) provide diagnostic expertise according to the latest guidelines, (iii) develop innovative approaches, (iv) provide cell types and stem cell support for ADRD research, and (v) promote durable ADRD research through support of ADRC Cores, development projects, and local and national research. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy individuals and those along the ADRD spectrum while ensuring proper safeguards.
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1 |
2021 |
Keene, Christopher Dirk |
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. |
Adult Changes in Thought (Act) Research Program Core D: Neuropathology Core @ Kaiser Foundation Research Institute
SUMMARY The Adult Changes in Thought (ACT) Neuropathology (NP) Core (Core D) has been a valuable and frequently utilized resource for the ACT cohort and supports the ACT Repository where the most generous gift to science ? a person?s brain ? is used to maximize impact on local and national science of Alzheimer?s disease and related dementias (ADRD). The NP Core has instituted rapid protocols designed for cutting edge molecular cell profiling and has markedly extended sampling strategies to better capture regional changes that underlie the heterogeneity of Alzheimer?s disease and related dementias. The NP Core has fostered development of innovative, highly quantitative approaches to assess the neuropathology of ADRD, building on this important tradition by integrating imaging technologies and analytical approaches to target and quantify gross and microscopic pathology. We perform post-mortem MRI on every brain, generate 3D virtual brain reconstructions leveraging unique brain sectioning techniques in the NP Core, scan slides of prospective and archival ACT samples for traditional quantitative image analysis supplemented with deep learning approaches to maximize information yield, and leverage multiplexed solution-phase assays from fixed-tissue protein extracts to compare cytoarchitectural and biochemical pathologic changes in ADRD. All of these innovations are designed to enable us to deeply characterize the structural substrate for ADRD heterogeneity, mechanisms of resilience and resistance, and the biological basis of cognitive subtypes and functional variations in brain aging and dementia in support of each of the ACT Cores. We combine this comprehensive analysis of human brains with a leptomeningeal cell resource and neuropathological characterization for mechanistic explorations of AD pathophysiology (Project 3) and promote existing collaborations focused on characterizing cell type vulnerabilities in all stages of AD to inform mechanistic, diagnostic, and therapeutic research. The NP Core interacts with and supports every other ACT U19 Research Program Core and Project through state-of-the-art diagnostics and has expanded dissection and assessment protocols specifically tailored to support Project 2. Thus, our Aims reflect our commitment to integrate traditional diagnostic excellence and extensive tissue and data sharing with radiographically informed extensive sampling and a battery of highly quantitative, molecularly specific tissue and in silico approaches to precisely measure ADRD neuropathology. Our specific Aims are to (1) build a highly accessible repository of brain tissue and fluids, (2) provide diagnostic expertise according to the latest guidelines, (3) develop innovative approaches, and (4) promote durable ADRD research through support of ACT Cores and Projects. All of our research activities are focused on enhancing the research value of tissue and body fluid donations from cognitively healthy ACT participants and those along the ADRD spectrum while ensuring proper safeguards.
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0.907 |
2021 |
Kaeberlein, Matt [⬀] Keene, Christopher Dirk |
R24Activity Code Description: Undocumented code - click on the grant title for more information. |
Developing the Privately Owned Companion Dog as a Model For Alzheimers Disease @ University of Washington
Alzheimer?s disease and other dementias represent an increasing burden on society, with an estimated 5.8 million Americans suffering from Alzheimer?s disease. A major barrier to progress in Alzheimer?s disease research is a lack of suitable animal models that (1) show pathological hallmarks and clinical features similar to those seen in patients with Alzheimer?s disease, and (2) have similar genetic and environmental heterogeneity to people. The privately-owned companion dog uniquely captures both of these features. The Dog Aging Project (DAP) is a consortium of investigators with the shared goal of understanding the biological aging process, including age-related cognitive changes and dementia, in companion dogs through large-scale longitudinal study and clinical evaluation of putative healthspan-promoting interventions. More than 50,000 companion dogs will ultimately be enrolled in the DAP Pack, for which detailed owner survey information is collected annually, including the gold standard cognitive assessment questionnaire for diagnosis of canine cognitive dysfunction (CCD). A high-resolution ?Precision Group? of 1,000 dogs are being studied in much greater depth, including full genome sequencing, veterinarian-reviewed electronic medical records (VEMRs), and annual assessments including physical exam, clinical chemistry, blood epigenome, serum metabolome, and fecal microbiome. We propose to synergistically leverage the infrastructure of the DAP to create an unparalleled and one-of-a-kind resource for studying Alzheimer?s-like disease in the companion dog. To accomplish this goal, we will (1) recruit 200 dogs with CCD into a ?CCD Precision Group? which will be studied at high resolution in parallel with the cognitively normal DAP Precision Group, including assessments of serum abundance of AD markers such as Ab42, Tau, and hyperphosphorylated Tau, (2) quantitatively assess proteomic and neuropathological hallmarks of Alzheimer?s-like disease in brains from 100 companion dogs who reach the end of their natural lives, and (3) create a large canine data and biospecimen repository to support future studies of Alzheimer?s-like disease in companion dogs. We anticipate that successful completion of this project will not only create a rich dataset on AD-like disease in companion dogs, but will also spur numerous follow-on studies by other investigators. It is our hope and expectation that these resources will have a major impact on Alzheimer?s disease research far into the future.
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1 |
2021 |
Eisenberg, David Kayed, Rakez [⬀] Keene, Christopher Dirk Kuret, Jeff A |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Interdisciplinary Research Network On Biologically Active Tau Aggregate Polymorphs From Alzheimer's Disease and Related Dementias @ University of Texas Med Br Galveston
PROJECT SUMMARY Tau aggregation is a shared pathology of Alzheimer's disease and related dementias known as tauopathies. Because each disorder develops a unique combination of aggregate polymorphisms and co-morbidities that may influence the course and severity of disease, elucidating the relationship between tau aggregate structure and biological activity has become a high priority in the field. Advances to date have been limited, however, by the lack of rigorously standardized aggregate preparations from each form of tauopathy and by the absence of tools needed to selectively detect their presence in biological models and clinical specimens. The proposed Interdisciplinary Research Network on Biologically Active Tau Aggregate Polymorphs seeks to address this need by (1) isolating a full range of biologically active tau aggregates from authentic Alzheimer's disease, Corticobasal Degeneration, Progressive Supranuclear Palsy, and Pick's disease brain tissue, (2) establishing their structures through biophysical analysis, (3) developing probe sets for their selective detection, and (4) disseminating reliably vetted samples and lab-ready protocols for their handling and storage to the broader research community. In accomplishing these goals, the network will support research into the molecular basis of tauopathy pathogenesis and catalyze efforts toward creating novel diagnostic and therapeutic strategies specifically tailored against toxic tau aggregate polymorphs.
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0.943 |