U19AG074866

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

(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.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Pittsburgh, Pennsylvania 15213 United States

Single Zip Code

Complex Integrated Multi-Component Projects in Aging Research (U19 Clinical Trial Optional) (PAR-19-374)

Amendment Since initial award the total obligations have increased 386% from $5,845,166 to $28,395,368.