Defining the Contribution of Placental Macrophage Polarization and Iron-Handling to the Progression of Gestational Diabetes Mellitus

 描述(申请人提供)：妊娠期糖尿病(GDM)是妊娠期最常见的代谢紊乱，会导致相当大的发病率和母婴的长期并发症。减少妊娠期糖尿病发病率和负担的一个主要障碍是缺乏对导致疾病发病和严重程度的潜在病理生理机制的了解。虽然异常的全身性炎症与妊娠期糖尿病有关，但导致这种炎症的因素尚未阐明。众所周知，巨噬细胞在调节全身和局部炎症环境中发挥着广泛的作用，并负责体内80%的铁(Fe)利用率。巨噬细胞结合极化状态和对铁处理和可用性的炎症反应。例如，促炎巨噬细胞隔离铁，而抗炎巨噬细胞采用铁循环表型，导致铁释放增加。CD163仅在巨噬细胞上表达，并被用作胎盘巨噬细胞的标志物(PMϕS)，它介导血红蛋白-结合珠蛋白(Hb：HP)复合体的内吞和随后的分解，启动依赖于血红素加氧酶的抗炎信号通路。尽管有这些众所周知的关联，但关于Fe和PMϕS在胎盘中的相互作用知之甚少。在这项建议中，我们将比较妊娠期糖尿病和健康胎盘在PM、ϕ、炎症情况和铁状态方面的差异。令人惊讶的是，很少有人研究妊娠期糖尿病如何改变PMϕ表型和胎盘炎症，特别是在铁处理方面。我们推测：(1)PmϕS从人和小鼠健康胎盘中分离出来，表现出抗炎特性，并积极参与铁的处理，这与妊娠期糖尿病患者PmϕS积聚铁并表现出促炎表型相反。(2)高铁饮食会增加Pmϕ铁的积聚和胎盘炎症，从而增加妊娠期糖尿病的发病率和严重程度。我们计划通过一系列综合的具体目标来检验这些假设。首先，我们将表征妊娠期糖尿病患者和健康受试者PMϕS的铁处理状态和激活状态(目标1)。接下来，我们将表征妊娠期糖尿病小鼠PMϕS的铁处理状态和激活状态(目标2)。最后，我们将确定不同数量的膳食铁如何影响胎盘炎症GDM进展(目标3)。我们将定义妊娠期糖尿病是如何影响PMϕS的炎症和铁处理状态的。此外，这些实验将阐明改变膳食铁水平对妊娠期糖尿病发病率和严重性的影响，为未来专注于改变膳食铁以改善母婴健康的研究奠定基础。总之，这项研究的结果将为更好地了解妊娠期糖尿病如何影响胎盘炎症以及铁在妊娠期糖尿病的发展和进展中的作用奠定基础。

 DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy causing considerable morbidity and long-term complications for both mother and child. A major barrier to reducing the incidence and burden of GDM is a lack of clarity regarding the underlying pathophysiological mechanisms contributing to the pathogenesis and severity of the disease. Although aberrant systemic inflammation has been associated with GDM, the factors that contribute to this inflammation have not yet been elucidated. Macrophages are known to play an extensive role in regulating both systemic and local inflammatory environments as well as being responsible for 80% of the Iron (Fe) availability within the body. Macrophages couple polarization status and inflammatory responses to Iron-handling and availability. For example, pro-inflammatory macrophages sequester Fe while anti-inflammatory macrophages adopt an Iron- cycling phenotype resulting in increased Fe release. Exclusively expressed on macrophages and used as a marker of placental macrophages (pMϕs), CD163 mediates the endocytosis and subsequent breakdown of hemoglobin-haptoglobin (Hb:Hp) complexes initiating a heme-oxygenase-dependent anti-inflammatory signaling pathway. Despite these well-known associations, little is known regarding the interactions between Fe and pMϕs within the placenta. In this proposal we will compare GDM and healthy placentae in terms of pMϕ inflammatory profile and Fe status. Surprisingly, little work has been done to investigate how GDM alters pMϕ phenotypes and placental inflammation, especially in terms of Iron-handling. We hypothesize that (i) pMϕs isolated from human and murine healthy placenta display anti-inflammatory characteristics and are actively engaged in Iron-handling in contrast to subjects with GDM where pMϕs accumulate Fe and display a pro-inflammatory phenotype (ii) high dietary Fe will increase pMϕ Fe accumulation and placental inflammation leading to an increase in the incidence and severity of GDM. We plan to test these hypotheses through a series of integrated Specific Aims. First, we will characterize the Iron-handling status and activation state of human pMϕs from GDM and healthy subjects (Aim 1). We will next characterize the Iron- handling status and activation state of murine pMϕs in GDM (Aim 2). Finally, we will determine how varying amounts of dietary Fe affect placental inflammation GDM progression (Aim 3). We will define how GDM influences the inflammatory and Iron-handling status of pMϕs. Furthermore, these experiments will elucidate the impact of altered dietary Fe levels on the incidence and severity of GDM laying the groundwork for future studies focused on modifying dietary Fe to improve maternal-child health. Together, results from this proposal will lay the groundwork for a better understanding of how GDM affects placental inflammation and the role of iron in the development and progression of GDM.