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.

项目概要 产前早期在子宫内接触性类固醇已被证明会改变胎儿的发育 一些临床前研究已经证实了这一点。 研究表明，母体雄激素暴露与胎儿生长发育迟缓有关 妊娠期间，胎盘是成年后代的心脏代谢紊乱的主要器官。 事实上，从母亲向胎儿提供营养、氧气和激素，会导致不良的胎儿结局。 鉴于雄激素，已知长期健康风险的规划具有胎盘起源。 受体在人类胎盘中表达，有人提出雄激素可以改变正常的 因此，这些观察结果强调了胎盘损害的合理性。 怀孕时暴露于过量的雄激素，这可能是胎儿发育的一种机制 成年后的生长受限和随后的心脏代谢失调 该研究计划将调查怀孕期间母体雄激素与 胎盘功能的病理标志物并确定其对预测心脏代谢的影响 新英格兰历史性合作项目参与者的母子成年后罹患的疾病 围产期项目（1959-1966）鉴于胎盘解剖和生长的性别差异，它 还必须了解胎盘功能的变化如何影响男性与女性 因此，该提案还将调查性别。 产前雄激素对胎盘影响的差异尚未得到充分证实 了解产前雄激素对胎盘的影响。 系统可能会导致针对胎盘功能障碍的新的性别特异性治疗方法 怀孕并改善母亲及其后代一生的健康。 Grace Huang 博士（首席研究员）是布莱根妇女医院医学助理教授 她和哈佛医学院的 K08 研究已经在一项研究中提供了纵向证据。 人类模型表明妊娠雄激素环境的改变可以产生终生编程 拟议的 R03 项目将对后代代谢健康产生影响。 以这些发现为基础，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规划的潜在机制。 这些将是对 PI 可以访问和熟悉的已收集数据的二次分析 这些研究结果将共同提供有力的初步数据支持。 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 参与成人心血管疾病的早期规划及其整个生命周期中潜在的性别差异。