Dysregulation of maternal immunity during pregnancy by pregravid obesity

孕前肥胖导致孕期母亲免疫力失调

• 批准号: 10237898
• 负责人: Ilhem Messaoudi
• 金额: $ 4.58万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237898
• 关键词: 37 weeks gestation; Address; Biology; Birth; Blood; Blood specimen; Body mass index; Cell physiology; Cells; Cesarean section; Chronic; Data; Decidua; Dendritic Cells; Development; Epigenetic Process; Equilibrium; Exhibits; Female of child bearing age; Fetal Growth; Frequencies; Functional disorder; Genetic Transcription; Gestational Age; Gestational Diabetes; Growth; Growth and Development function; Health; Heterogeneity; Homeostasis; Host Defense; Immune; Immune system; Immunologics; Immunology; Impaired wound healing; Impairment; Induced Labor; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune System; Investigation; Laboratories; Lead; Ligands; Link; Macrophage Activation; Maintenance; Maternal-Fetal Exchange; Maternal-fetal medicine; Maternally-Acquired Immunity; Metabolic; Metabolism; Modeling; Molecular; Mothers; Natural Killer Cells; Obesity; Outcome; Phagocytes; Phenotype; Placenta; Placentation; Play; Positioning Attribute; Pre-Eclampsia; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Publishing; Risk; Role; Sampling; Statistical Models; Surgical Wound Infection; Systems Biology; Testing; Thinness; Third Pregnancy Trimester; Time; Tissues; Villous; Woman; adverse outcome; adverse pregnancy outcome; age related; antimicrobial; cell type; comorbidity; epidemiology study; epigenome; experimental study; fetal; functional genomics; healthy pregnancy; insight; intraamniotic infection; macrophage; monocyte; next generation sequencing; novel; obese mothers; peripheral blood; pregnancy hypertension; prepregnancy obesity; recruit; response; surgical risk; wound healing

Successful pregnancy requires carefully coordinated changes in the immune system that facilitate placentation, promote fetal tolerance and growth, and induce labor. Deviations from this tightly regulated “pregnancy immunological clock” can lead to as pre-eclampsia and complications during labor. The rates of obesity amongst women of childbearing age have increased at an alarming rate, making it one of the most common comorbidities during pregnancy. Previously published studies and our preliminary data indicate an enhancement of monocyte response to LPS between 12 and 37 weeks of gestation Importantly, our preliminary analyses indicate that maternal pregravid body mass index (BMI) >30 abrogates this pregnancy-associated monocyte activation. This observation provides a potential explanation for the increased susceptibility to infections and poor wound healing outcomes observed in obese pregnant women. We hypothesize that chronic low grade inflammation induced by pregravid obesity disrupts the gestational age dependent monocyte activation, skewing them to an immunotolerant phenotype. Additionally, given that macrophages in the decidua are recruited from circulating monocytes, we will investigate the burden of obesity on phenotype and function of decidual macrophages. We further hypothesize that pregravid obesity results in a hyper-inflammatory phenotype within decidual macrophages. We will employ a multi-dimensional approach to test these hypotheses. The novelty of this application lies in the systems biology approach that integrates phenotypic, functional, and genomic readouts longitudinally in peripheral blood and at term in the placenta. Completion of the proposed experiments will reveal the molecular mechanisms that explain progressive changes in monocyte activation over the course of healthy pregnancy, and how that is disrupted with obesity.

成功怀孕需要免疫系统精心协调的变化，以促进胎盘，