This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $159,492 to Weill Medical College of Cornell University to develop tools for identifying somatic variants associated with clonal expansions in aging and age-related diseases, and to characterize the epigenetic landscape of these clonal variants. The project aims to leverage machine learning to analyze public RNA-sequencing data to discover somatic variants linked to conditions like diabetes,...
This Project Grant award from the National Institute on Aging (NIA), under the Aging Research program (CFDA 93.866), provides $255,420 to The Trustees of the University of Pennsylvania to conduct research on "Balancing Cellular Repair and Regeneration in Aging and Disease". The key objectives are to: 1) delineate the mechanism of Hedgehog signaling in balancing autophagy and proliferation to preserve cellular aging; 2) define the Hedgehog-dependent transcriptome during aging, with a...
The National Institute on Aging (NIA) awarded a $422,419 Project Grant (CFDA 93.866 - Aging Research) to the University of California, Los Angeles (UCLA) to understand the cellular mechanisms that enable tissue and cellular rejuvenation. The research aims to map the changes in the transcriptome, chromatin landscape, transcription factor binding, and epigenetic age across partial cellular reprogramming induced by the OSKM transcription factors. This is expected to identify gene-regulatory and...
The National Institute on Aging (NIA), under the Aging Research federal grant program (CFDA 93.866), awarded a $506,404 project grant to The Trustees of the University of Pennsylvania to conduct research on the role of chromatin and epigenetic mechanisms in regulating senescence and aging. The 5-year project (1/1/2025 - 12/31/2029) will investigate: 1) how enhancer rewiring and the formation of large enhancer communities drive gene expression changes during senescence; 2) the mechanisms behind...
This National Institute on Aging (CFDA 93.866 Aging Research) Project Grant award of $412,500 to the Trustees of Boston University (Boston University Medical Campus) will fund research to investigate the "vicious cycle" between disruption of chromatin architecture, activation of retrotransposable elements (RTEs), and misexpression of CpG island-deficient genes during the aging process. The research aims to validate the mutual activation between chromatin architecture disruption and RTE...
This $485,375 Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) will fund research at the University of Washington to investigate genomic alterations in skeletal muscle associated with aging. The key objectives are to: Explore if alternative splicing of mRNA results in quantitative differential isoform changes associated with aging, potentially leading to increased expression of non-functional proteins relevant for healthy muscle function. The researchers...
This Project Grant award of $395,796 from the National Institute on Aging's Aging Research program (CFDA 93.866) supports research at Brown University to develop genetic, pharmacological, and dietary interventions that delay the onset and progression of age-related diseases. The key objectives are to: 1) Investigate the interconnectedness and hierarchical structure of the hallmarks of aging, such as loss of genomic integrity, activation of retrotransposons, and accumulation of lipid droplets; 2)...
This Project Grant award of $400,000 was provided by the National Institute on Aging (CFDA 93.866 - Aging Research) to The Trustees of the University of Pennsylvania. The award will fund research to develop computational methods for measuring intrinsic biological noise in single-cell sequencing data across levels of chromatin accessibility, gene expression, and transcript splicing. The research aims to investigate the relationship between epigenetic, transcriptional, and splicing noise and...
This federal Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $173,788 to the University of California, Los Angeles (UCLA) to conduct a 5-year research program focused on understanding mitochondrial genome mutations that contribute to human tissue aging, with a specific focus on skin tissue. The key objectives of the research are to: 1) map and determine the tissue specificity of mitochondrial DNA (mtDNA) mutations in aged skin, 2) quantify mtDNA...
This Project Grant award for $866,764 from the National Institute on Aging's Aging Research Program (CFDA 93.866) supports an interdisciplinary research study at the University of California, San Francisco (UCSF) to investigate human-specific vulnerabilities and compensatory adaptations of midbrain dopaminergic neurons in response to age-related stressors. The project aims to leverage stem cell-derived organoids, primary tissue samples, machine learning, and CRISPR techniques to directly measure...
DISCRIMINATING BETWEEN CAUSES OF AGE-RELATED VARIEGATED GENE EXPRESSION - PROJECT SUMMARY: CELLS IN THE SAME TISSUE CAN EXPRESS THE EXACT SAME GENE AT DIFFERENT LEVELS, AND THIS CELL-TO-CELL VARIATION TENDS TO INCREASE WITH AGE. CELLS IN TISSUES NEED TO COORDINATE GENE EXPRESSION TO MAINTAIN HOMEOSTASIS. THUS, DYSREGULATED VARIATION MAY BE RELATED TO, OR CAUSATIVE OF, THE LOSS OF PHYSIOLOGICAL CAPACITIES WITH AGE. HOWEVER, THE CAUSES AND CONSEQUENCES OF THIS INCREASED GENE EXPRESSION VARIATION ARE NOT KNOWN. IN THIS PROJECT I PROPOSE TO USE C. ELEGANS AND HUMAN TISSUE CULTURE AS MODEL SYSTEMS TO STUDY AGE-RELATED VARIATION IN GENE EXPRESSION BETWEEN HOMOLOGOUS CELLS IN CONTROLLED ENVIRONMENTS. IN OUR PRIOR STUDY, WE FOUND STRONG, CELL-SPECIFIC EXPRESSION PATTERNS FOR MANY REPORTER GENES IN YOUNG C. ELEGANS ANIMALS; THAT IS, FOR MANY GENES IN YOUNG ANIMALS, THE RATIO OF GENE A TO GENE B EXPRESSION WAS FIXED IN CELL TYPE X, AND DIFFERENT THAN IN CELL TYPE Y. WE FOUND THAT THIS FIXED EXPRESSION PATTERN DETERIORATES WITH AGE; IN A GIVEN CELL TYPE GENES BECOME EXPRESSED AT VARIABLE STOICHIOMETRY IN INDIVIDUAL ANIMALS. SIMILARLY, IN MAMMALS, CELL-TO-CELL VARIATION IN GENE EXPRESSION OBSERVED DURING AGING OR SENESCENCE IS ALSO UNCORRELATED. THUS, I PROPOSE THAT GROWING DISSIMILARITY BETWEEN HOMOLOGOUS CELLS WITH AGE MAY BE A CONSERVED PHENOMENON OF AGING. I REFER TO INCREASE OF UNCORRELATED GENE EXPRESSION VARIATION WITH AGE AS AGE-RELATED VARIEGATED GENE EXPRESSION (VGE). IN THE PROPOSED PROJECT, I WILL HARNESS BOTH THE POWER OF C. ELEGANS AND HUMAN CELL CULTURE TO INVESTIGATE HOW HOMOLOGOUS CELLS BECOME MORE DISSIMILAR WITH AGE. IN THE K99 PHASE OF THE PROJECT I WILL LEARN TECHNIQUES FOR QUANTITATIVE MICROSCOPY, SINGLE CELL RNASEQ AND AGING-FOCUSED HUMAN CELL CULTURE METHODS. THROUGHOUT THE K99 AND R00, I WILL BE INVESTIGATING POTENTIAL CAUSES THAT CONTRIBUTE TO AGE-RELATED VGE. K99-AIM1: I WILL DETERMINE IF CHANGES OF ALLELE ACCESS WITH AGE CONTRIBUTE INTO VGE IN C. ELEGANS BY ANALYZING EXPRESSION FROM OF IDENTICAL PROMOTERS INTEGRATED AT THE IDENTICAL LOCI ON SISTER CHROMOSOMES. K99-AIM2: I WILL LEARN AND USE SINGLE-CELL RNA-SEQ TO DETERMINE IF PREVALENCE OF ALLELE BIAS/MONOALLELISM RISES IN HUMAN FIBROBLASTS WITH AGE. R00-AIM3: I WILL DETERMINE WHAT GENES AND PATHWAYS BECOME HIGHLY VARIABLY EXPRESSED WITH AGE. I WILL EXAMINE IF VARIABLE EXPRESSION OF THESE GENES IS STOCHASTIC OR ADAPTIVE BY DETERMINING IF EXPRESSION LEVELS OF REPORTERS OF THESE GENES PREDICT STRESS RESISTANCE, HEALTH OR LIFESPAN. THESE EXPERIMENTS WILL ADDRESS THE HYPOTHESIS THAT ADAPTIVE PHYSIOLOGICAL RESPONSES OF INDIVIDUAL CELLS TO AGE-RELATED STRESS CONTRIBUTE TO VGE. R00-AIM 4: USING HUMAN CELL CULTURE, I WILL DETERMINE IF CELL-TO-CELL COMMUNICATIONS PROPAGATE VGE AMONG CELLS WITH YOUTHFUL EXPRESSION PATTERNS - THAT IS, CELLS WITHOUT VGE.