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

• 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
• 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

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.

对衰老何时开始的理解，衰老如何改变细胞和组织，以及 正常衰老转化为病理事件的机制是基本的 生物学的重要性，是美国国家老龄研究所的任务的核心。 对这一过程的洞察力是至关重要的，并且有可能影响健康和疾病 整个生活范围。为了满足这种需求，我们提出了一个新的范式来了解 通过使用胎儿组织发展作为模型的生理和病理衰老机制 由于宫内寿命是有限的。我们使用人类胎儿膜的初步研究 （羊膜和绒毛膜）体外和体内动物模型表明端粒依赖性， p-p38mapk，p21，p19arf的逐步增加和胎儿半乳糖苷酶染色的增加 膜在学期达到峰值。我们已经表明，此过程与“无菌”有关 炎症与相关的秘密表型（SASP）一致。那 胎儿膜经历了一个发展计划，其中包括许多 传感的分子标志。基于我们的体外数据，氧化应激（OS） 由不同的刺激引起的引起差异机械激活 在人类胎儿膜中，我们假设胎儿​​可以用作模型 描述病理生理学机制以及生理介质的机制的系统 感应。在此R21应用中，我们的总体目标是开发鼠标模型 进一步描述了胎儿膜中的感应表型，并测试OS在此中的作用 过程。我们向我求婚。检验以下假设，即缺乏或改变关键组成部分的假设 感应途径会破坏胎儿膜体内稳态，并破坏正常的 分娩。 ii。描述内源性OS调节剂在与感应相关的 分娩的基础机制。 iii确定了外源诱导的效率 抗氧化作用在抑制胎儿组织感应中。 获得的洞察力将有助于开发一个模型，从中获得更好的了解 体内倡议和早期调节的基础机制。而且， 提出的研究将使我们能够建立一个OS诱导的感应模型，这可能是 适用于许多成人代谢，自身免疫和心血管疾病。