Document text
Principal Investigator: Gregory W Carter
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $6,287,895
Funding agency: National Institute on Aging
PROJECT SUMMARY OVERALL
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting nearly 6 million Americans and
is expected to increase over the next several years. Our limited understanding of the mechanisms that trigger
the emergence of AD has contributed to the lack of interventions that stop, prevent, or fully treat this disease.
We propose to establish the marmoset as the first primate-specific model to reveal the earliest cellular and
molecular events of AD processes and allow charting AD progression from its inception. To do so, we will draw
from a self-sufficient and large colony of research marmosets with dedicated veterinary and husbandry teams,
state-of-the-art in vivo neuroimaging and molecular assays, and a multidisciplinary team of experts in aging
biology, AD genetics and genomics, animal model development and characterization, behavioral and cognitive
phenotyping, and marmoset gene-editing technologies. Our proposal’s overarching goals are to develop
marmoset models of early-onset AD (EOAD) and late-onset AD (LOAD) to enable the investigation of the
underlying cellular and molecular root causes of the pathogenesis and progression of AD and support future
translational studies. We believe that the simultaneous assessment of genetic, molecular, functional, behavioral,
and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of
AD in human populations. Furthermore, we posit that the comprehensive study of gene-edited marmoset models
of AD from neurodevelopment through aging will identify emerging phenotypes that precede frank
neuropathology. Our proposal consists of 3 integrated Research Projects that aim to: (1) Conduct
characterization and validation of PSEN1 mutations in marmosets as a model for the study of EOAD, and
investigate early life molecular determinants of AD disease pathogenesis associated with genetic risk for EOAD;
(2) Identify and enhance LOAD-related signatures in outbred and genetically-engineered marmosets; and (3)
Conduct a comparative multimodal phenotypic characterization of marmoset models of AD. These projects will
be supported by 5 Research Cores focused on project administration, bioinformatics, genetic engineering,
multimodal disease characterization, and veterinary and colony management. These supporting cores will
integrate marmoset and human genomic signatures and provide data dissemination and resources to the greater
research community as part of our commitment to open science, generate novel gene-edited marmoset models
of AD, develop optimized protocols for studying disease onset and trajectory in line with clinical protocols,
evaluate therapeutic strategies, and provide specialized animal care and support, respectively, allowing
complete characterization of the marmoset models. At the conclusion of this project, we will have genetically
engineered three AD risk variants into marmoset models, established a disease characterization pipeline for
comprehensive phenotyping, and shared these resources with the greater research community.
Terms: <AD dementia><AD model><Acceleration><Affect><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimer's disease risk><Alzheimers Dementia><Amentia><American><Assay><Behavioral><Bio-Informatics><Bioassay><Bioinformatics><Biological><Biological Assay><Biology of Aging><Biometrics><Biometry><Biostatistics><Brain><Brain Nervous System><California><Callithrix><Clinical Protocols><Cognitive><Communities><Computational Biology><Data><Dedications><Degenerative Neurologic Disorders><Dementia><Disease><Disease Progression><Disorder><EOAD><Early Onset Alzheimer Disease><Encephalon><Equipment><Evaluation><Event><Exhibits><Future><Gene variant><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Risk><Genetic defect><Genomics><Goals><Hapale><Human><Image><Intervention><Intervention Strategies><Investigation><Investigators><Knowledge><Late Onset Alzheimer Disease><Life><Link><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Marmosets><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><NMR Imaging><NMR Tomography><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural Development><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Nuclear Magnetic Resonance Imaging><Onset of illness><Outcome><PET><PET Scan><PET imaging><PET/CT><PET/CT scan><PETSCAN><PETT><PSEN1><Pathogenesis><Pathologic><Patients><Phenotype><Population><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Primates><Primates Mammals><Process><Protocol><Protocols documentation><R-Series Research Projects><R01 Mechanism><R01 Program><Rad.-PET><Radiation Chemistry><Radiochemistry><Recombinant DNA Technology><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Resources><Researchers><Resource Sharing><Resources><Risk Factors><Risk-associated variant><S182 protein><Short-Tusked Marmoset><Study models><The Jackson Laboratory><Therapeutic><Universities><Validation><Work><Zeugmatography><allele variant><allelic variant><alzheimer model><alzheimer risk><analytical method><animal care><animal model development><assault><biologic><comparative><computer biology><data dissemination><data integration><data resource><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease onset><disorder onset><early onset AD><early onset Alzheimer's><gene editing platform><gene editing system><gene editing technology><gene editing tools><gene-editing toolkit><genetic condition><genetic disorder><genetic variant><genetically engineered><genome mutation><genomic classifier><genomic signature><genomic variant><imaging><in vivo><interventional strategy><late onset alzheimer><model organism><multi-modality><multidisciplinary><multimodality><neural imaging><neuro-imaging><neurodegenerative illness><neurodevelopment><neuroimaging><neurological imaging><neuropathologic><neuropathological><neuropathology><novel><open data><open science><open-source data><positron emission computed tomography><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><presenilin 1 protein><presenilin-1><prevent><preventing><primary degenerative dementia><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><senile dementia of the Alzheimer type><statistics><tool><translational study><ultrasound><validations>