Investigating The Role Of The Maternal Androgen Milieu On Placental Function: A Potential Mechanism For Programming Of Fetal Growth Restriction And Cardiometabolic Dysregulation In Adulthood

研究母体雄激素环境对胎盘功能的作用：胎儿生长受限和成年期心脏代谢失调的潜在机制

• 批准号: 10347630
• 负责人: Grace Huang
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347630
• 关键词: Address; Adult; Adult Children; Adverse effects; Anatomy; Androgen Receptor; Androgens; Birth; Birth Weight; Blinded; Blood Circulation; Blood Vessels; Cardiometabolic Disease; Cardiovascular Diseases; Childhood; Complement; Data; Data Analyses; Development; Endocrine; Exposure to; Familiarity; Family Study; Female; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Funding; Future; Goals; Gonadal Steroid Hormones; Growth; Growth and Development function; Health; Hormones; Hospitals; Human; Hypertension; Immunologics; Impairment; Lead; Lesion; Life; Life Cycle Stages; Longevity; Longitudinal cohort; Longitudinal cohort study; Low Birth Weight Infant; Measures; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolic Syndrome X; Metabolic syndrome; Mission; Modeling; Mothers; National Heart, Lung, and Blood Institute; New England; Nutrient; Organ; Outcome; Outcome Measure; Oxygen; Participant; Pathologic; Pathologist; Pathology; Perinatal; Placenta; Placental Insufficiency; Play; Pre-Clinical Model; Pregnancy; Pregnant Women; Research; Research Proposals; Risk; Risk Factors; Role; Serum; Sex Differences; Surrogate Markers; System; Testosterone; Therapeutic; Third Pregnancy Trimester; Tissues; Vascular resistance; Vascularization; Weight; Woman; androgen excess; base; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; critical developmental period; epigenetic marker; fetal; fetal programming; fetus hypoxia; follow-up; health of the mother; human model; improved; in utero; longitudinal analysis; male; medical schools; new therapeutic target; offspring; placental morphology; preclinical study; prenatal; prenatal exposure; prenatal influence; professor; programs; response; secondary analysis; sex; wasting

Project Summary Early prenatal exposure to sex steroids in utero has been shown to alter fetal developmental trajectory and induce cardiometabolic pathologies in adulthood. Several preclinical studies have shown that maternal androgen exposure is associated with reduced fetal growth and development of cardiometabolic disorders in the adult offspring. During pregnancy, the placenta is the main organ supplying nutrients, oxygen, and hormones from mother to fetus. Indeed, adverse fetal outcomes and programming of long-term health risks are known to have placental origins. Given that androgen receptors are expressed in human placenta, it has been proposed that androgens can modify normal placental function. Thus, these observations highlight the plausibility of placental compromise in pregnancies exposed to excess androgens, which may be a mechanism for programming of fetal growth restriction and subsequent cardiometabolic dysregulation in adult life This research proposal will investigate the relationship of maternal androgens during pregnancy with pathologic markers of placental function and determine their impact on predicting cardiometabolic diseases in adulthood among mother-offspring New England participants of the historic Collaborative Perinatal Project (1959-1966). Given the sex differences in the anatomy and growth of the placenta, it is also imperative to understand how changes in placental function impacts male versus female offspring in response to prenatal androgen exposure. Thus, this proposal will also investigate the sex differences in the effects of prenatal androgens on the placenta which has not be adequately addressed in previous studies. Understanding the influence of prenatal androgens on the placental system could lead to new sex-specific therapeutic approaches to target placental dysfunctions during pregnancy and improve the health of mothers and their offspring across the lifespan. Dr. Grace Huang (the PI) is an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School. Her K08 studies have already provided longitudinal evidence in a human model that alterations in the gestational androgen milieu can have life-long programming effects on the metabolic health of the offspring that is sex-dependent. The proposed R03 project will build upon these findings and examine the sex-dependent impact of prenatal androgens on the placenta, as a potential mechanism for long-term programming of adult cardiometabolic diseases. These will be secondary analyses of data already collected that the PI has access to and familiarity with analyzing. Together, the results of these studies will provide strong preliminary data supporting an R01 application to further investigate the androgen-mediated mechanisms and epigenetic markers involved in early programming of adult CVD and their underlying sex differences across the lifespan.

项目摘要 已经证明，早期产前暴露于子宫内性类固醇会改变胎儿发育 成年期轨迹和诱导心脏代谢病理。一些临床前研究有 表明母乳雄激素暴露与胎儿生长的降低和发育有关 成人后代的心脏代谢疾病。怀孕期间，plapeta是主要器官 从母亲到胎儿提供营养，氧气和激素。确实，不良胎儿结果和 已知长期健康风险的编程具有胎盘起源。鉴于那个雄激素 受体在人的plapeta中表达，已经提出雄激素可以改变正常 胎盘功能。这是，这些观察凸显了胎盘妥协的合理性 暴露于过量雄激素的怀孕，这可能是编程胎儿的机制 成人生活中的生长限制和随后的心脏代谢失调 该研究建议将调查孕妇在怀孕期间与 位置功能的病理标记并确定其对预测心脏代谢的影响 历史合作的新英格兰参与者的成年疾病 围产期项目（1959-1966）。鉴于安置的解剖结构和生长的性别差异， 还必须了解装置功能的变化如何影响男性与女性 响应产前雄激素暴露的后代。那，该提议还将调查性别 产前雄激素对bopeta的影响的差异，而胎盘尚未充分 在先前的研究中解决。了解产前雄激素对位置的影响 系统可能会导致新的性别治疗方法，以靶向靶向装置功能障碍 怀孕并改善母亲的健康及其在整个生命周期的健康。 Grace Huang博士（PI）是Brigham and Hospital的医学助理教授 和哈佛医学院。她的K08研究已经在 妊娠雄激素环境改变的人类模型可以具有终身节目 对性依赖性的后代代谢健康的影响。拟议的R03项目将 基于这些发现并检查产前雄激素对性别的影响 胎盘，作为成人心脏代谢疾病长期编程的潜在机制。 这些将是对已经收集的数据的次要分析，PI已可以访问和熟悉 进行分析。总之，这些研究的结果将提供强大的初步数据支持 R01应用程序进一步研究雄激素介导的机制和表观遗传标记 参与了成人CVD的早期编程及其在整个生命周期中的基本性别差异。