Document text
Principal Investigator: PETER D. ADAMS
Organization: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Fiscal Year: 2024
Award: $514,488
Funding agency: National Institute on Aging
PROJECT SUMMARY
Chromatin is a key determinant of cell phenotype and function. Therefore, chromatin stability over the lifespan
is presumably a pre-requisite for maintenance of cell and tissue phenotype and function, and hence healthy
aging and longevity. However, chromatin is not a static fixed structure, but is a dynamic and plastic “breathing”
assembly. As a dynamic and plastic entity, chromatin is prone to change or drift, a process likely exacerbated
by intrinsic cellular processes and extrinsic/environmental influences. Therefore, this dynamic chromatin likely
represents a challenge for a cell to achieve phenotypic stability, healthy aging and longevity, especially for long-
lived cells. In other words, given their dynamic chromatin, how do healthy human neurons and cardiomyocytes
remain as such for decades? To explain this, we have proposed that cells possess mechanisms of chromatin
homeostasis, or chromostasis, that preserve chromatin integrity, suppress phenotypic instability or “plasticity”,
and so slow the pace of aging and promote healthy aging. We will test this hypothesis as follows:
Specific Aim 1. Test whether altered nucleosome stability affects features of chromostasis and cell phenotypic
plasticity.
Specific Aim 2. Identify candidate chromostasis genes and small molecule modulators and test their impact on
cell phenotypic plasticity.
Specific Aim 3. Test whether enhanced chromostasis promotes healthy aging and longevity.
This proposal is broadly significant because it will reveal basic mechanisms of physiological chromatin/epigenetic
control and how this impinges on healthy aging and longevity, pathological states such as cell transformation,
and therapeutic applications such as cell reprogramming. Accordingly, this proposal can have a major impact on
scientific understanding and human health by revealing: 1) mechanisms that underlie stable cell phenotype; 2)
biomarkers of age-associated degeneration and predisposition to disease; 3) targets for interventions to promote
healthy aging, prevent degenerative disease and cancer, and facilitate therapeutic cell reprogramming.
Terms: <AD dementia><ATAC sequencing><ATAC-seq><ATACseq><Affect><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Bioassay><Biological Assay><Body Tissues><Breathing><Cancers><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Aging><Cell Body><Cell Function><Cell Growth and Maintenance><Cell Maintenance><Cell Physiology><Cell Process><Cell Reprogramming><Cell Senescence><Cells><Cellular Aging><Cellular Function><Cellular Physiology><Cellular Process><Cellular Senescence><Chromatin><Coin><Degenerative Disorder><Disease><Disorder><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Explosion><FRET><Fluorescence Resonance Energy Transfer><Förster Resonance Energy Transfer><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Screening><Genetic defect><Genetic screening method><Health><Heart Muscle Cells><Heart myocyte><Heterogeneity><Histones><Homeostasis><Human><In Vitro><Intervention><Intervention Strategies><Length of Life><Life Cycle><Life Cycle Stages><Logic><Longevity><Maintenance><Malignant Neoplasms><Malignant Tumor><Measures><Modern Man><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nucleosomes><Pathologic><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Predisposition><Primary Senile Degenerative Dementia><Process><Rationalization><Replicative Senescence><Respiratory Aspiration><Respiratory Inspiration><Structure><Subcellular Process><Susceptibility><Testing><Therapeutic><Time><Tissues><Variant><Variation><age associated biomarkers><age associated decline><age associated marker><age dependent decline><age marker><age related biomarkers><age related decline><age related markers><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><biological markers of age><biomarkers of age><candidate identification><cardiomyocyte><cell transformation><cell type><cellular reprogramming><chemical genetics><decline with age><degenerative condition><degenerative disease><epigenetically><epigenome><genome mutation><healthy aging><healthy human aging><in vivo><innovate><innovation><innovative><insight><inspiration><interventional strategy><life course><life span><lifespan><malignancy><mutant><neoplasm/cancer><neuronal><novel><pace of aging><pace of biological aging><preservation><prevent><preventing><primary degenerative dementia><programs><rate of aging><rate of biological aging><restraint><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell technology><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule><speed of aging><speed of the aging><tool><transcriptomics><transformed cells>