Rubicon: a novel target of sex-specific placental dysfunction in maternal obesity

Rubicon：孕产妇肥胖中性别特异性胎盘功能障碍的新靶标

• 批准号: 10000193
• 负责人: Alina Maloyan
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-22 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000193
• 关键词: Address; Adult; Affect; Amino Acid Transporter; Autophagocytosis; Binding; Biotin; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Cysteine-Rich Domain; Data; Development; Diet; Environment; Female; Fetal Growth; Fetal health; Fetus; Functional disorder; Future Generations; Generations; Growth and Development function; Health; Human; Immune; Impairment; Inflammation; Inflammatory; Knowledge; Laboratories; Life; Link; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Molecular; Nuclear; Obesity; Obesity Epidemic; Overweight; Pathologic; Pattern recognition receptor; Phagocytosis; Placenta; Placental Hormones; Pregnancy; Process; Proteins; Proteomics; Public Health; Recycling; Reporting; Research; Role; Sex Differences; Signal Transduction; Small Interfering RNA; TNF gene; Therapeutic; Viral Vector; Weight; Woman; adverse outcome; base; chromatin immunoprecipitation; cytokine; experimental study; fetal; in utero; inhibition of autophagy; insight; loss of function; male; maternal obesity; novel; obesogenic; offspring; overexpression; prevent; programs; protein protein interaction; response; role model; sedentary lifestyle; sex; stressor; targeted treatment; therapeutic target; transcription factor; trophoblast

PROJECT SUMMARY More than 65% of women entering pregnancy in the US are overweight or obese. Obesity in pregnancy predisposes the offspring to obesity, and cardiovascular and metabolic disorders, thus initiating a “vicious cycle” of obesity and its health-related consequences in subsequent generations even in the absence of further intrauterine stressors. The worldwide epidemic of obesity and cardiovascular and metabolic diseases, therefore, is not only a result of the sedentary lifestyle or poor diet; it is also a consequence of a “developmental program” switched on as a result of an adverse in utero environment. The absence of therapeutic strategies to prevent developmental programming is a consequence of our lack of knowledge of the mechanisms whereby maternal obesity affects the health of future generations. The placenta is a crucial determinant of healthy fetal growth and development, but the consequences of obesity for placental health are only now beginning revealed. Data from our laboratory have shown an accumulation of inflammatory cytokine TNFα in the placentas of female fetuses is associated with an activation of pro-inflammatory transcription factor nuclear factor κappa B (NFκB). Inflammation is tightly regulated by autophagy, a cellular recycling process, and unresolved inflammation has been associated with a disruption of autophagy, which, in turn, leads to cardiovascular and metabolic diseases. Our recent data suggest that placentas of both male and female offspring from obese women show inhibition of autophagy. However, there are significant sex differences in the mechanisms. In the placentas of males, inhibition of autophagy is associated with a decrease in critical autophagy coordinating transcription factor EB. In the placentas of females, in contrast, inhibition of autophagy is linked to inflammation via Rubicon (RUN domain and cysteine-rich domain containing Beclin1- interacting protein), a newly identified negative regulator of autophagy. We found an increase in Rubicon expression and Beclin 1 binding in the placentas of females of obese women with this phenomenon not seen in placentas of males. Our data suggest that these processes are, at least in part, regulated by TNFα-induced inflammation. Here we hypothesize that in response to inflammation generated in utero by maternal obesity, an increase in placental Rubicon expression occurs causing changes in its protein-protein interaction and thereby inhibiting placental autophagy. We will address this hypothesis with three specific aims: 1). Identify the mechanisms that regulate expression of Rubicon and its binding to Beclin1 in the human placenta with maternal obesity. 2). Determine the molecular basis relating Rubicon to the inhibition of autophagy in the placenta with obesity. 3). Identify sex-dependent mechanisms that regulate Rubicon signaling in the placenta with maternal obesity. This study will provide mechanistic insights that will systematically and rigorously fill these gaps and thereby open the opportunity for the development of Rubicon-based therapies to address the adverse consequences of maternal obesity for offspring, a major unmet public health need.

项目概要 在美国，超过 65% 的怀孕女性在怀孕期间体重超重或肥胖。 使后代容易出现肥胖、心血管和代谢紊乱，从而引发“恶性循环” 即使没有进一步的研究，肥胖的循环”及其对后代健康相关的影响 子宫内压力源。全球肥胖、心血管和代谢疾病的流行， 因此，这不仅是久坐的生活方式或不良饮食的结果； “发育程序”由于子宫内环境不利而启动。 阻止发育规划的治疗策略是我们缺乏知识的结果 因此，孕产妇肥胖影响子孙后代健康的机制。 胎儿健康生长和发育的决定因素，但肥胖对胎盘健康的影响 我们实验室的数据现在才开始显示炎症细胞因子的积累。 女性胎儿胎盘中的 TNFα 与促炎转录的激活有关 核因子 κappa B (NFκB) 炎症受到自噬（一种细胞循环）的严格调节。 过程中，未解决的炎症与自噬的破坏有关，反过来， 我们最近的数据表明，男性和女性的胎盘都会导致心血管和代谢疾病。 肥胖女性的雌性后代表现出自噬抑制，但存在显着的性别差异。 在男性胎盘中，自噬的抑制与自噬的减少有关。 相反，在女性胎盘中，关键的自噬协调转录因子 EB 受到抑制。 自噬通过 Rubicon（RUN 结构域和含有 Beclin1- 的富含半胱氨酸结构域）与炎症相关 蛋白质相互作用），一种新发现的自噬负调节因子，我们发现 Rubicon 有所增加。 肥胖女性胎盘中的表达和 Beclin 1 结合，这种现象在 我们的数据表明，这些过程至少部分受到 TNFα 诱导的调节。 在这里，我们一直在努力应对母亲肥胖在子宫内产生的炎症， 胎盘 Rubicon 表达的增加导致其蛋白质-蛋白质相互作用发生变化，从而 我们将通过三个具体目标来解决这一假设：1）。 调节人胎盘中 Rubicon 表达及其与 Beclin1 结合的机制 母亲肥胖2)。确定Rubicon与抑制自噬相关的分子基础。 肥胖胎盘3)。 这项研究将提供系统性、严格性的机制见解。 这些差距，从而为开发基于 Rubicon 的疗法提供了机会，以解决 孕产妇肥胖对后代的不利后果是一项未得到满足的重大公共卫生需求。