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

确定胎盘巨噬细胞极化和铁处理对妊娠期糖尿病进展的贡献

• 批准号: 9053605
• 负责人: Theresa Leigh Barke
• 金额: $ 2.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053605
• 关键词: Adipose tissue; Adopted; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Characteristics; Child; Complex; Data; Development; Diet; Dietary Iron; Disease; Disease Marker; Endocytosis; Environment; Environmental Risk Factor; Future; Gene Expression; Gestational Diabetes; Health Status; Homeostasis; Human; Immunophenotyping; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intake; Iron; Liver; Maternal and Child Health; Maternal-Fetal Exchange; Mediating; Metabolic Diseases; Morbidity - disease rate; Mothers; Mus; Nature; Oxygenases; Pathogenesis; Pathology; Patients; Phenotype; Placenta; Play; Population; Pregnancy; Production; Role; Series; Severities; Severity of illness; Signal Pathway; Spleen; Testing; Work; defined contribution; fetal; haptoglobin-hemoglobin complex; heme a; improved; macrophage; mortality; mouse model; novel; public health relevance; research study

 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.