Generation, Characterization, and Validation of Marmoset Models of Alzheimer's Disease

阿尔茨海默病狨猴模型的生成、表征和验证

• 批准号: 10494769
• 负责人: Gregory W Carter
• 金额: $ 584.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494769
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Animal Model; Behavioral; Bioinformatics; Biological; Biological Assay; Biology of Aging; Biometry; Brain; California; Callithrix; Clinical Protocols; Cognitive; Communities; Computational Biology; Data Analytics; Dementia; Disease; Disease Progression; Early Onset Alzheimer Disease; Equipment; Evaluation; Event; Exhibits; Future; Generations; Genes; Genetic; Genetic Diseases; Genetic Engineering; Genetic Risk; Genomics; Goals; Human; Image; Institutes; Intervention; Investigation; Knowledge; Late Onset Alzheimer Disease; Life; Link; Magnetic Resonance Imaging; Modeling; Molecular; Mus; Mutation; Neurodegenerative Disorders; Onset of illness; Outcome; PET/CT scan; Pathogenesis; Pathologic; Patients; Phenotype; Plant Roots; Population; Positron-Emission Tomography; Primates; Process; Protocols documentation; Radiochemistry; Research; Research Personnel; Research Project Grants; Resource Sharing; Resources; Risk Factors; Study models; Technology; The Jackson Laboratory; Therapeutic; Universities; Validation; Work; analytical method; animal care; animal model development; assault; comparative; data dissemination; data integration; data resource; genetic variant; genomic signature; in vivo; molecular imaging; multidisciplinary; multimodality; neurodevelopment; neuroimaging; neuropathology; novel; open data; presenilin-1; prevent; risk variant; statistics; tool; translational study; ultrasound

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.

项目概况