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Cellular senescence and epigenomic remodeling in ovarian aging

卵巢衰老中的细胞衰老和表观基因组重塑

基本信息

批准号：
10091665
负责人：
Michael B Stout
金额：
$ 34.51万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10091665
关键词：
Age Age-Months Age-Years Aging Alleles Animal Model Attenuated Biochemical Caloric Restriction Cell Aging Cell Separation Cells Chromatin Chronic Disease Chronology Clinical DNA DNA Damage DNA Methylation Data Databases Development Dwarfism Elderly Embryo Emerging Technologies Encapsulated Endocrine Enhancers Enterobacteria phage P1 Cre recombinase Epigenetic Process Excision Female Gene Expression Genetic Genetic Transcription Genome Genomics Germ Cells Goals Growth Health Benefit Histologic Human Infiltration Inflammation Mediators Inflammatory Intervention Knowledge Laboratories Link Longevity Menopause Modeling Modification Molecular Mus Nucleic Acids Oocytes Ovarian Ovarian Granulosa Cell Ovarian aging Ovariectomy Ovary Ovulation Pattern Pharmacology Pharmacotherapy Phenotype Play Population Pregnancy Primordial Follicle Process Production RNA Reporting Research Resources Role Scientific Advances and Accomplishments Sirolimus Source Stress Testing Time TimeLine Tissues Transcript Transgenic Organisms Work age related body system burden of illness cell injury cell type epigenomics exhaustion functional decline genetic manipulation granulosa cell healthspan in vivo macrophage nonhuman primate novel ovarian dysfunction ovarian failure preservation prevent pup reproductive reproductive fitness reproductive senescence senescence theca cell transcription factor transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Declines in ovarian function are closely associated with reductions in healthspan and longevity. Numerous studies have linked ovarian dysfunction to systemic organismal aging, although very little is known with regard to the basic, intrinsic mechanisms that initiate and perpetuate age-related ovarian functional declines. These knowledge gaps represent a critical barrier to developing treatments aimed at attenuating age-related ovarian failure. Ovarian aging is characterized by the progressive depletion of quiescent primordial follicles, which eventually leads to irregular patterns of ovulation and disruption of the ovarian endocrine milieu. This project will systemically explore how cell-type specific changes in cellular senescence and epigenetics/genomic organization contribute to age-related ovarian failure through the use of novel transgenic NuTRAP models that allow for the isolation of nucleic acids (DNA & RNA) specifically from oocytes, granulosa cells, or theca cells without the need for cell sorting. Successful completion of this project will determine: 1) what role cellular senescence and epigenetic modifications play in primordial follicle exhaustion, 2) if age-related cellular senescence and epigenetic modifications occur in a cell-type specific fashion along differing timelines, 3) if epigenetic changes precede or follow the emergence of cellular senescence, and 4) if the removal of senescent cells and/or the suppression of the SASP through senolytic drug treatment can extend reproductive lifespan. We hypothesize that granulosa cells encapsulating primordial follicles accumulate deleterious cellular and epigenetic alterations, undergo a senescence-like transition, and thereby accelerate primordial follicle growth and maturation, thereby leading to exhaustion. We will test this hypothesis through following aims. Specific Aim 1: Characterize cell type-specific changes in markers of cellular senescence in oocytes, granulosa, and theca cells from the aging ovary. We predict that senescence cell burden and inflammatory mediators will increase with advancing age and that granulosa cells are a major source of this phenotype. Specific Aim 2: Characterize cell type-specific changes in epigenetic alterations and transcriptional profiles within oocytes, granulosa, and theca cells from the aging ovary. We predict that the majority of age-related changes will be cell-specific and that `epigenetic clocks' of distinct cell types advance at different rates. We also anticipate that granulosa cells will display the greatest changes in epigenetic and transcriptional profiles and that this will correspond to declines in ovarian primordial follicle reserve. Aim 3: Determine if the clearance of senescent cells within the ovary restores ovarian function and prolongs reproductive fitness. We predict that senolytic treatment will increase the number of primordial follicles and that oocytes will accumulate less DNA damage with chronological aging. We also anticipate that this will result in a greater production of embryos with less DNA damage, thereby increasing the number of pregnancies, litters, and pups born to older female mice. The ultimate goal of this research is to develop clinical interventions that extend reproductive lifespan for systemic health benefits.

项目总结/文摘