Mechanotransduction mechanisms of ovarian aging
卵巢衰老的机械传导机制
基本信息
- 批准号:10703383
- 负责人:
- 金额:$ 12.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-12 至 2023-09-29
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAccelerationAffectAgeAgingAneuploidyAnimal ModelArchitectureBehaviorBiochemicalBiomechanicsCellsCellular StructuresCharacteristicsCollagenCompetenceComplementCritical ThinkingCuesDeteriorationDevelopmentDiestrusDown-RegulationEncapsulatedEngineeringEnvironmentEstrogensEstrous CycleEstrusExtracellular MatrixFemaleFertilityFoundationsGene Expression ProfileGenetic TranscriptionGoalsGrantGrowthHormonalHumanHyaluronanHydrogelsIn VitroInfertilityKineticsLinkMapsMeasuresMediatingMetestrusMissionMolecularMusNational Institute of Child Health and Human DevelopmentOocytesOrganOvarianOvarian agingOvarian hormoneOvaryPathologicPathway interactionsPhysical environmentPhysiologicalPolycystic Ovary SyndromePositioning AttributePostdoctoral FellowPrimordial FollicleProcessProestrusProgesteronePropertyResearchResolutionScientistSignal TransductionStructureSystemTestingTissuesTrainingUnited States National Institutes of HealthWomanWorkadvanced maternal agecareercell behaviorcorpus luteumfemale fertilityfemale reproductive systemgranulosa cellinsightloss of functionmechanical propertiesmechanical signalmechanotransductionmouse modelnoveloocyte qualityreproductivereproductive senescencespatiotemporalthree dimensional structuretransmission process
项目摘要
PROJECT SUMMARY
Aging affects all tissues and is associated with functional deterioration. Each tissue has specific aging kinetics,
and the female reproductive system is the first to age. Female reproductive aging is associated with a decrease
in oocyte quality and quantity as well as a reduction in the ovarian hormones, which accelerates women
physiologic aging. Reproductive transitions, such as reproductive aging, are a priority of the Fertility and Infertility
branch of the National Institutes of Health, and thus my proposed research is tightly aligned with the mission of
the Eunice Kennedy Shriver National Institute of Child Health and Human Development. A major contributor to
the age-associated reduction of female fertility is the decrease in oocyte quality due to an increase in oocyte
aneuploidy, but our work and others have demonstrated that other factors, such as the tissue microenvironment,
might contribute to the age-associated reduction in oocyte quality. Physical cues from the tissue environment
are major regulators of cell behavior. In the ovary, stiffness is relevant for normal follicle development but also
associated with pathological conditions. In mice, stiff environments maintain primordial follicles in a quiescent
state. However ovarian stiffness is also a characteristic of polycystic ovarian syndrome in humans. In my
postdoctoral work I pioneered the use of instrumental indentation to measure the biomechanical properties of
the ovary and I found that mice ovaries become stiffer with advanced reproductive age. My work on ovarian
stiffness laid the foundation of this proposal where I will test the overarching hypothesis that the age-associated
and spatially-dependent increase in ovarian stiffness creates a physical environment that impacts follicle
development and oocyte quality through activation of mechanotransduction pathways in the follicle. This
hypothesis will be tested in three specific aims. First, I will determine the subcellular features that define ovarian
stiffness by performing a 3D spatio-temporal architecture map of the ovarian stiffness in an age and estrous
cycle dependent manner. Second, I will investigate how stiffness affects follicle development and oocyte
competency at the transcriptional and cellular level. I will establish an in vitro system which enables precise
control of the physical environment. Third, I will explore the mechanism by which the follicle integrates the
physical cues and whether the dysregulation of this mechanism accelerates reproductive aging. I will investigate
whether follicles from reproductively young and old mice have the same capacity to respond to physical cues
through the activation of mechanotransduction pathways, focusing on YAP1. I will complement these studies
with in vitro loss-of-function approaches and a YAP1 engineered animal model. Overall, this research will define
the ovary’s mechanical properties as a novel regulatory mechanism of reproductive aging. Finally, the research
and career developmental plan proposed here are integral to enhance my scientific training and critical thinking
and accomplish my goal of becoming an independent scientist in the field of reproductive aging.
项目总结
项目成果
期刊论文数量(0)
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会议论文数量(0)
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