Impact of the Placenta Barrier on Fetal Nutrition and Growth Restriction

胎盘屏障对胎儿营养和生长限制的影响

• 批准号: 10471436
• 负责人: Danielle Kozlosky
• 金额: $ 4.17万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471436
• 关键词: ABCG2 gene; Address; Anatomy; Biology; Blood Circulation; Cadmium; Cadmium chloride; Catabolism; Cellular Stress; Chemicals; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Disease; Doctor of Philosophy; Dose; Down-Regulation; Educational workshop; Environment; Environmental and Occupational Exposure; Etiology; Exposure to; Fellowship; Fetal Growth Retardation; Fetal Weight; Fetal health; Fetus; Genes; Genetic Polymorphism; Gestational Age; Glucose; Glucose Transporter; Growth; Heavy Metals; Histopathology; Homeostasis; Human; Hypoglycemia; Image; Immunohistochemistry; Impairment; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Infant Mortality; Joints; Knowledge; Label; Laboratories; Lead; Link; Maternal Exposure; Measurable; Mediating; Membrane; Metals; Modeling; Molecular Profiling; Molecular Target; Mus; Newborn Infant; Nutrient; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Placenta; Placentation; Play; Pregnancy; Pregnant Women; Prevalence; Proteins; Reporting; Reproductive Biology; Research; Resistance; Risk; Rodent; Role; Scientist; Series; Severities; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stains; Stress; Techniques; Testing; Time; Tissue Banks; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Training; Training Activity; Transgenic Mice; Transgenic Organisms; Universities; Variant; Visualization; Wild Type Mouse; Xenobiotics; efflux pump; epidemiology study; fetal; fetus nutrition; imager; in vivo; infant morbidity; innovation; loss of function; molecular transporter; nutrition; overexpression; perinatal development; pregnant; programs; protein expression; reproductive; response; toxicant; translational approach; trophoblast

PROJECT SUMMARY/ABSTRACT Fetal growth restriction (FGR) is a critical disease that contributes significantly to infant mortality and morbidity. Although the etiology of FGR is poorly understood, environmental and occupational exposures have been implicated in its pathogenesis. Measurable levels of the environmental toxicant cadmium (Cd) have been found in >99% of pregnant women. This widespread exposure is important as Cd has been shown to induce FGR in rodents and linked to FGR in human epidemiological studies. Cd targets key functions of the placenta that lead to FGR. Under healthy conditions, the placenta critically regulates nutrient exchange between the maternal and fetal circulation while at the same time restricts the transfer of toxicants. Efflux pumps, including the breast cancer resistance protein (human BCRP/rodent Bcrp), are highly expressed on the maternal-facing membrane of placentas and thus aid in fetal protection by lowering placental (and fetal) xenobiotic concentrations. Our laboratory has demonstrated that in vitro overexpression of the human BCRP gene lowers intracellular Cd concentrations and confers resistance against Cd cellular stress and toxicity. However, it is unknown whether Bcrp in the placenta can regulate Cd toxicity in vivo. To begin to address this question, I have developed a model of Cd-induced FGR in wild-type mice. Preliminary data reveal a decrease in fetal weights that is accompanied by a decline in fetal glucose levels following administration of CdCl2 to pregnant mice. These data align with prior studies suggesting that nutrient transporters are molecular targets of Cd-induced FGR. My central hypothesis is that placentas with a complete loss or reduction in Bcrp transporter function are at a heightened risk of Cd accumulation which leads to impaired glucose transfer and utilization and severe fetal growth restriction. I will utilize two transgenic mouse lines to test this hypothesis: 1) Bcrp-/- mice that have no Bcrp expression and 2) Bcrp-Q140K mice, a CRISPR model that is orthologous to the human loss-of-function Q141K variant and recapitulates the reduced functioning of BCRP observed clinically. I anticipate that placentas from Bcrp-/- and Bcrp-Q140K mice will be more sensitive to Cd accumulation and toxicity compared to wild-type (Bcrp+/+) mice which will be tested in two specific aims. For this fellowship, I will complete a series of training in rodent and clinical anatomic pathology of the placenta, coursework and workshops in reproductive biology and toxicology, and hands-on experimental techniques including ICP/MS and immunohistochemistry. The majority of the training activities will occur at Rutgers University through the interdisciplinary Joint Graduate Program in Toxicology. Overall, this proposed research plan will enhance my development into an independent research scientist through studies completed as part of a Ph.D. dissertation.

项目总结/摘要 胎儿生长受限（FGR）是一种严重的疾病，导致婴儿死亡率和发病率显着。 尽管对FGR的病因学知之甚少，但环境和职业暴露已被证实。 与其发病机制有关。环境毒物镉（Cd）的可测量水平已被发现 >99%的孕妇。这种广泛的接触是重要的，因为镉已被证明会诱导FGR， 在人类流行病学研究中与FGR有关。镉靶向胎盘的关键功能， 到FGR。在健康的条件下，胎盘严格地调节母体和母体之间的营养交换。 胎儿循环，同时限制毒物的转移。外排泵，包括乳腺癌 耐药蛋白（人BCRP/啮齿动物BCRP），高度表达于 胎盘，从而通过降低胎盘（和胎儿）异生素浓度来帮助保护胎儿。我们 一个实验室已经证明，在体外过表达的人BCRP基因降低细胞内镉 浓度和赋予抗镉细胞应激和毒性。然而，不知道是否 胎盘中的Bcrp可调节体内镉毒性。为了开始解决这个问题，我开发了一个模型 镉诱导的FGR在野生型小鼠。初步数据显示，胎儿体重下降， 妊娠小鼠给予氯化镉后，胎儿葡萄糖水平下降。这些数据与之前的 研究表明营养转运蛋白是镉诱导FGR的分子靶点。我的核心假设是 Bcrp转运蛋白功能完全丧失或降低的胎盘， 这导致葡萄糖转移和利用受损以及严重的胎儿生长受限。我会 利用两个转基因小鼠系来检验这一假设：1）没有Bcrp表达的Bcrp-/-小鼠和2） Bcrp-Q140 K小鼠，一种与人类功能丧失Q141 K变体直向同源的CRISPR模型， 概括了临床观察到的BCRP功能降低。我预计来自Bcrp-/-和 与野生型（Bcrp+/+）小鼠相比，Bcrp-Q140 K小鼠对Cd蓄积和毒性更敏感 将在两个特定目标中进行测试。为了这个奖学金，我将完成一系列的啮齿动物培训， 胎盘的临床解剖病理学，生殖生物学和毒理学的课程和讲习班， 和动手实验技术，包括ICP/MS和免疫组织化学。大部分培训 活动将通过跨学科的毒理学联合研究生项目在罗格斯大学进行。 总的来说，这个建议的研究计划将促进我发展成为一个独立的研究科学家 作为博士学位的一部分完成的研究论文