Novel Roles of Placental Allopregnanolone in Brain Development and Injury

胎盘四氢孕酮在大脑发育和损伤中的新作用

• 批准号: 9367396
• 负责人: ANNA A PENN
• 金额: $ 36.75万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9367396
• 关键词: Accounting; Acute; Adult; Allopregnanolone; Anatomy; Area; Autistic Disorder; Behavior; Behavioral; Birth; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Injuries; Cell Proliferation; Cerebral Palsy; Cognition Disorders; Cognitive deficits; Cre-LoxP; Data; Development; Embryo; Endocrine; Epilepsy; Excision; Fetal Development; Fetus; Functional disorder; Gases; Gene Deletion; Gene Expression; Gene Proteins; Generations; Genes; Goals; Hippocampus (Brain); Hormonal; Hormones; Human; Immunohistochemistry; Impairment; Infection; Inflammation; Injury; Investigation; Life; LoxP-flanked allele; Mass Spectrum Analysis; Measures; Mediating; Mental disorders; Modeling; Molecular Models; Neonatal; Neurologic; Neurological outcome; Neuroprotective Agents; Neurosecretory Systems; Nutritional; Outcome; Perinatal; Pharmacology; Physiological; Placenta; Placental Hormones; Pre-Eclampsia; Predisposition; Pregnancy; Premature Birth; Premature Infant; Production; Progesterone; Proliferating; Psyche structure; Research; Risk; Rodent; Role; Safety; Seizures; Shapes; Site; Source; Stem cells; Steroids; System; Testing; Therapeutic Agents; Time; Tissues; analog; base; brain abnormalities; defined contribution; design; disability; experimental study; fetal; fetal brain injury; fetus at risk; flexibility; gamma-Aminobutyric Acid; ganaxolone; high risk; hormone deficiency; hormone therapy; in vivo; molecular modeling; mouse model; neglect; neocortical; nervous system disorder; neurogenesis; neuroprotection; neurosteroids; novel; novel therapeutics; offspring; postnatal; pre-clinical; premature; prenatal; prevent; protein expression; public health relevance; small hairpin RNA; subventricular zone; synthetic enzyme; tool

ABSTRACT Compromised placental function is highly associated with abnormal fetal development, especially of the brain. Abnormal brain development or fetal brain injury leads to life-long neurological impairments, including cerebral palsy, seizures and mental disabilities. Placental dysfunction may place many thousands of fetuses at risk of life-long impairments each year. The vast majority of research connecting placental compromise to fetal brain injury has focused on gas exchange or nutritional programming, neglecting the placenta's essential neuroendocrine role. Using new molecular models, we are testing our overall hypothesis that key placental hormones contribute to normal brain development and that their loss contributes to injury. One such critical placental hormone is allopregnanolone (ALLO), the most potent GABAergic neurosteroid derived from progesterone. In both rodent and human gestation, ALLO is made predominantly by the placenta. Our preliminary experiments have shown that pharmacological ALLO reduction during gestation disrupts cortico-hippocampal circuit maturation and alters GABAergic subunit expression. Additionally, endogenous and exogenous ALLO provides neuroprotection in multiple preclinical injury models. To use ALLO as a perinatal therapeutic agent, however, it is critical to understand the specific source, physiological levels and actions of ALLO in gestation. Until now, these investigations have been limited by lack of tools designed to precisely alter and measure placental neurosteroids, barriers we have overcome through generation of new mouse models and use of advanced mass spectroscopy. We have generated mouse models in which ALLO production is suppressed only in placenta. These models allow direct placental steroid manipulation for the first time. We have shown that suppression of placental ALLO production results in a specific reduction of proliferating intermediate progenitor cells (IPCs) in the cortical subventricular zone during gestation and that there are long-lasting functional neurological alterations after placental ALLO is suppressed. Using our new floxed mouse model (AKR1c14fl/fl) in which the gene for 3αHSD can be deleted in a tissue-specific manner, we will determine the extent to which placental ALLO is critical to: 1) corticogenesis; 2) long-term behavior and circuit function; and 3) injury that may be amenable to perinatal treatment. Elucidation of the mechanisms by which placental hormones, including ALLO, shape normal and abnormal cortical development would fundamentally change our understanding of developmental brain disorders and the placenta's role in shaping long-term neurological outcomes. These experiments also provide the possibility to prevent or ameliorate developmental brain injury through novel therapies based on placental hormones.

抽象的 胎盘功能受损与胎儿发育异常，尤其是大脑发育异常密切相关。 大脑发育异常或胎儿脑损伤会导致终生神经损伤，包括脑瘫、 癫痫发作和精神障碍。胎盘功能障碍可能使数以千计的胎儿面临终生危险 每年都有减值。绝大多数研究将胎盘损害与胎儿脑损伤联系起来 专注于气体交换或营养规划，忽视了胎盘的重要神经内分泌 角色。使用新的分子模型，我们正在测试我们的总体假设，即关键胎盘激素 有助于正常的大脑发育，而它们的丧失会导致受伤。一个这样重要的胎盘 激素是四氢孕酮 (ALLO)，是源自黄体酮的最有效的 GABA 能神经类固醇。在 无论是啮齿类动物还是人类妊娠期，ALLO 主要由胎盘产生。我们的初步实验 研究表明，妊娠期间药物性 ALLO 减少会扰乱皮质-海马回路 成熟并改变 GABA 亚基表达。此外，内源性和外源性 ALLO 提供 多种临床前损伤模型中的神经保护。然而，使用 ALLO 作为围产期治疗剂， 了解妊娠期 ALLO 的具体来源、生理水平和作用至关重要。到目前为止， 这些研究因缺乏旨在精确改变和测量胎盘的工具而受到限制 神经类固醇，我们通过生成新的小鼠模型和使用先进的技术克服了障碍 质谱法。我们已经生成了小鼠模型，其中 ALLO 的产生仅在 胎盘。这些模型首次允许直接胎盘类固醇操作。我们已经证明 抑制胎盘 ALLO 的产生会导致增殖中间体的特异性减少 妊娠期间皮质室下区的祖细胞（IPC）并且存在持久 胎盘 ALLO 被抑制后功能性神经系统改变。使用我们新的 floxed 鼠标模型 （AKR1c14fl/fl），其中 3αHSD 的基因可以以组织特异性方式删除，我们将确定 胎盘 ALLO 在多大程度上对以下方面至关重要：1) 皮质生成； 2）长期行为和电路功能； 3) 可能适合围产期治疗的损伤。阐明其机制 胎盘激素，包括 ALLO，塑造正常和异常的皮质发育 从根本上改变我们对发育性大脑疾病和胎盘在塑造大脑中的作用的理解 长期神经系统结果。这些实验还提供了预防或改善的可能性 通过基于胎盘激素的新疗法来治疗发育性脑损伤。