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: 10213791
• 负责人: ANNA A PENN
• 金额: $ 33.34万
• 依托单位: COLUMBIA UNIVERSITY 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: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213791
• 关键词: Accounting; Acute; Adult; Allopregnanolone; Anatomy; Area; Behavior; Behavioral; Birth; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Injuries; 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; 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; Steroids; System; Testing; Therapeutic Agents; Time; Tissues; analog; autism spectrum disorder; 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; stem cell proliferation; stem cells; 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.

摘要 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身神经功能障碍，包括脑瘫， 癫痫和精神残疾胎盘功能障碍可能会使成千上万的胎儿处于终身危险之中。 每年都有损伤。绝大多数将胎盘损害与胎儿脑损伤联系起来的研究 关注于气体交换或营养计划，忽视了胎盘的基本神经内分泌 作用使用新的分子模型，我们正在测试我们的总体假设，即关键的胎盘激素 有助于正常的大脑发育，它们的损失会导致损伤。一个如此关键的胎盘 激素是别孕烯醇酮（allopregnanolone，ALLO），其是来源于孕酮的最有效的GABA能神经类固醇。在 在啮齿动物和人类妊娠期间，ALLO主要由胎盘产生。我们的初步实验 已经表明，在妊娠期间药物ALLO减少会破坏皮质-海马回路， 成熟并改变GABA能亚基表达。此外，内源性和外源性ALLO提供了 在多种临床前损伤模型中的神经保护作用。然而，使用ALLO作为围产期治疗剂， 对了解妊娠期ALLO的具体来源、生理水平和作用至关重要。到现在为止， 这些研究由于缺乏设计用于精确改变和测量胎盘的工具而受到限制， 神经类固醇，我们已经克服了障碍，通过新的小鼠模型的产生和使用先进的 质谱法我们已经产生了小鼠模型，其中ALLO的产生仅在小鼠中被抑制。 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产生导致增殖中间体的特异性减少 祖细胞（IPC）在皮质脑室下区在妊娠期间，并有长期的 胎盘ALLO被抑制后的功能性神经改变。使用我们新的floxed鼠标模型 （AKR 1c 14 fl/fl），其中3αHSD基因可以以组织特异性方式缺失，我们将确定 胎盘ALLO对以下方面至关重要的程度：1）皮质生成; 2）长期行为和回路功能; 和3）可能适合于围产期治疗的损伤。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大脑发育障碍和胎盘在塑造大脑中的作用的理解， 长期的神经学结果。这些实验还提供了预防或改善 通过基于胎盘激素的新疗法治疗发育性脑损伤。