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

项目总结 在美国，超过65%的怀孕女性超重或肥胖。妊娠期肥胖 使后代容易肥胖、心血管和新陈代谢紊乱，从而引发一种 肥胖症的“周期”及其在后代中的健康相关后果 宫内压力源。肥胖症、心血管疾病和代谢性疾病的全球流行， 因此，这不仅仅是久坐不动的生活方式或不良饮食的结果；它也是一种 由于宫内环境不利，“发育计划”启动。不存在 预防发展规划的治疗策略是我们缺乏对 母亲肥胖影响子孙后代健康的机制。胎盘是至关重要的 胎儿健康生长和发育的决定因素，但肥胖对胎盘健康的后果是 现在才开始显露出来。我们实验室的数据显示炎性细胞因子积聚 女性胎儿胎盘中肿瘤坏死因子α与促炎转录的激活有关 核因子κAPPA B(核因子κB)。炎症受到自噬的严格控制，自噬是一种细胞循环 过程中，未解决的炎症与自噬的中断有关，这反过来， 会导致心血管和代谢疾病。我们最近的数据表明，男性和女性的胎盘 肥胖女性的雌性后代表现出对自噬的抑制。然而，有显著的性行为 机制上的差异。在男性胎盘中，自噬的抑制与减少有关 在关键的自噬中协调转录因子EB。相比之下，在女性胎盘中，抑制 自噬通过Rubcon(Run结构域和含有Beclin1-的富含半胱氨酸的结构域)与炎症有关 相互作用蛋白)，一种新发现的自噬负调控因子。我们发现卢比孔的数量有所增加 肥胖女性胎盘中Beclin-1的表达和结合 男性的胎盘。我们的数据表明，这些过程至少部分地受肿瘤坏死因子α诱导的调节。 发炎。在这里，我们假设，为了应对母体肥胖在子宫中产生的炎症， 胎盘RUBICON表达增加，导致其蛋白质-蛋白质相互作用发生变化，从而 抑制胎盘自噬。我们将以三个具体目标来解决这一假说：1)。找出 人胎盘组织中Rubcon的表达及其与Beclin1结合的调控机制 母体肥胖。2)。确定Rubons与抑制自噬相关的分子基础 肥胖的胎盘。3)。确定调节胎盘中Rubcon信号的性别依赖机制 母体肥胖症。这项研究将提供机械的见解，将系统和严格地填充 这些差距，从而为基于卢比肯的疗法的开发打开了机会，以解决 母亲肥胖对后代的不利后果，这是一个主要的未得到满足的公共卫生需求。

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.