U19AG069701

Biology and Pathobiology of ApoE in Aging and Alzheimer's Disease - Project Summary (ApoE U19: Overall)

The overarching goal of this U19 project is to comprehensively understand the biology and pathobiology of apolipoprotein E (ApoE) in aging and Alzheimer's disease (AD) to inform therapeutic strategies. The E4 allele of the ApoE gene (ApoE4) is the strongest genetic risk factor for AD, impacting 50-70% of all AD patients, while the E2 allele is protective compared to the common E3 allele. ApoE4 is also a strong risk factor for age-related cognitive decline and vascular cognitive impairment.

To integrate existing knowledge and address critical gaps, we propose a unified ApoE cascade hypothesis that the structural differences and related biochemical properties among the three ApoE isoforms initiate their differential effects on a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. Towards this, we have assembled a multi-disciplinary team to synergize expertise and resources across multiple institutions. By integrating five interactive projects and seven robust cores, we will create a nexus for ApoE-related aging research, sharing the knowledge, expertise, and resources with the broader scientific community.

Project 1 will work closely with Core B to address the structural and biochemical properties of the three ApoE isoforms to generate insights for functional outcomes. Projects 2, 3, and 4 will interactively study how ApoE isoforms expressed in astrocytes, microglia, or vascular mural cells impact lipid metabolism, glial and vascular functions, AD-related pathologies, and cellular and molecular pathways using conditional mouse models and systems-based approaches. These studies will generate cell type-specific ApoE/lipoprotein particles that will be collected through in vivo microdialysis for structural and biochemical studies.

Project 5 will carry out genomic and genetic analyses to identify modifiers of ApoE-related age at onset of AD. Studies in Projects 2-5 will be interactively supplemented by neuropathological studies using postmortem brains from healthy aging studies or with AD pathologies (Core C), biomarker studies using both human and mouse biospecimens (Core D), and functional studies using human iPSC-derived cellular and organoid models (Core E).

This U19 proposal is supported by a comprehensive multi-omics core (Core F) for centralized proteomics, lipidomics, and metabolomics studies on various animal and iPSC models, as well as human postmortem brains and fluid biospecimens. The bioinformatics, biostatistics, and data management core (Core G) will provide critical support for analyzing large datasets, including those from single-cell RNA-seq, and biostatistics support to ensure scientific rigor. Core G will also work closely with the administrative core (Core A) to maintain an ApoE web portal designated as EPAAD where knowledge, resources, and data will be shared with the scientific community. Core A will also organize an annual ApoE symposium to promote collaboration and engage the ApoE community.

As such, this U19 will drive a team-based effort to generate essential knowledge to guide disease-modifying therapies for AD and other aging-related conditions.

Mayo Clinic Jacksonville (A Nonprofit Corporation)

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]

Jacksonville, Florida 322241865 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 379% from $6,820,292 to $32,683,845.