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Fetal Membranes: An In-Vivo Model for Developmental Senescence and its Consequences

胎儿膜：发育衰老及其后果的体内模型

基本信息

批准号：
9789153
负责人：
ELIZABETH A. BONNEY
金额：
$ 19.58万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789153
关键词：
Address Adult Affect Age Aging Animal Model Antioxidants Autoimmune Diseases Biological Biological Aging Biological Models Biological Process Birth Cardiovascular Diseases Cells Cessation of life Chemicals Chorion Clinical Complex Data Development Diet Disease Elements Endocrine System Diseases Environment Event Fetal Development Fetal Growth Fetal Membranes Fetal Tissues Fetus Galactosidase Genetic Growth and Development function Health Homeostasis Human In Vitro Infant Infection Inflammation Inflammatory Interruption Investigation Life Lipopolysaccharides Longevity MAPK14 gene Malignant Neoplasms Mediating Mediator of activation protein Membrane Metabolic Diseases Mission Modeling Molecular Mus National Institute on Aging Nutritional Onset of illness Organism Outcome Oxidative Stress PPAR gamma Pathologic Pathology Pathway interactions Phenotype Physiological Placenta Pregnancy Premature aging syndrome Process Regulation Risk Role Smoking Specificity Stains Sterility Stimulus Sulforaphane Term Birth Testing Therapeutic Time Tissues Translating Uterus Vascular Diseases adverse outcome adverse pregnancy outcome aged amnion base beta-Galactosidase cell transformation cigarette smoke cruciferous vegetable environmental stressor experience experimental study fetal fetal programming in utero in vivo in vivo Model insight mouse model normal aging p19ARF pathological aging physiologic stressor premature programs response senescence telomere

项目摘要

The understanding of when aging begins, how aging transforms cells and tissues, and the mechanisms by which normal aging translates into pathological events is of fundamental biological importance and is central to the mission of the National Institute on Aging. Insight into this process is critically needed and has the potential to impact health and disease across the spectrum of life. To address this need, we propose a new paradigm to understand mechanisms of physiologic and pathologic aging by using fetal tissue development as a model since intrauterine life is time limited. Our preliminary studies using human fetal membranes (amnion and chorion) in vitro and in vivo animal models suggest a telomere-dependent, progressive increase in P-p38MAPK, p21, p19ARF and increase in Galactosidase staining of fetal membranes peaking at term. We have shown that this process is associated with “sterile” inflammation consistent with the senescence- associated secretory phenotype (SASP). Thus fetal membranes undergo a developmental program that comprises many of the molecular hallmarks of senescence. Based on our in vitro data that oxidative stress (OS) induced by distinct stimuli causes differential mechanistic activation of the senescence pathway in human fetal membranes, we hypothesize that the fetal membranes can be used as a model system to delineate the mechanisms of pathophysiologic as well as physiologic mediators of senescence. In this R21 application, our overall objective is to develop mouse models to further delineate the senescence phenotype in fetal membranes and to test the role of OS in this process. We propose to i. Test the hypothesis that deficiency or alteration of key components of the senescence pathway will disrupt fetal membrane homeostasis and undermine normal parturition. ii. Delineate the role of regulators of endogenous OS, in the senescence-associated mechanisms underlying parturition. iii Determine the efficacy of exogenous induction of antioxidant action in inhibiting fetal tissue senescence. The insight gained will help develop a model from which to obtain better understanding of the mechanisms underlying the initiation and early regulation of senescence in vivo. Moreover, the studies proposed will allow us to establish a model of OS- induced senescence that will likely be applicable in many adult-onset metabolic, autoimmune and cardiovascular diseases.

了解衰老何时开始，衰老如何改变细胞和组织，以及