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

University Of Vermont & St Agric College, Burlington VT

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Abstract

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.