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: 10171257
• 负责人: ANNA A PENN
• 金额: $ 34.02万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171257
• 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.

抽象的 损害的占地功能与胎儿发育异常，尤其是大脑高度相关。 脑发育异常或胎儿脑损伤会导致终身神经系统障碍，包括脑瘫， 癫痫发作和精神残疾。胎盘功能障碍可能会使数千名胎儿处于终身风险 每年减值。绝大多数研究将置换术与胎儿脑损伤联系起来 专注于天然气交换或营养编程，忽略了Plopeta的基本神经内分泌 角色。使用新的分子模型，我们正在测试关键胎盘马的总体假设 有助于正常的大脑发育，并且它们的损失会导致受伤。一个这样的关键位置 马酮是Allopregnanolone（Allo），这是源自孕酮的最潜在的GABA能神经类固醇。 啮齿动物和人类妊娠，Allo主要由plapeta制成。我们的初步实验 已经表明，妊娠期间的药理学同素降低会破坏皮质 - 海马电路 成熟并改变GABA能亚基的表达。另外，内源性和外源性Allo提供 多个临床前损伤模型中的神经保护。但是，要使用Allo作为围产期治疗剂 对于了解妊娠中Allo的特定来源，物理水平和行为至关重要。到目前为止， 这些调查受到缺乏旨在精确更改和测量位置的工具的限制 神经类固醇，我们通过生成新的鼠标模型克服的障碍并使用高级 质谱。我们已经生成了鼠标模型，其中仅抑制Allo生产 胎盘。这些模型首次允许直接的斑点类固醇操作。我们已经表明 胎盘生产的抑制导致增殖中间体的特异性降低 妊娠期间皮质下室内区域的祖细胞（IPC），并且存在持久 抑制斑点allo后功能性神经系统改变。使用我们的新型鼠标模型 （AKR1C14FL/FL）可以以组织特异性删除3αHSD的基因，我们将确定 lopenal Allo对以下层面至关重要的程度：1）皮质生成； 2）长期行为和电路功能； 3）可能会受到围产期治疗的伤害。阐明该机制 胎盘激素，包括Allo，形成正常和异常的皮质发育 从根本上改变了我们对发展脑疾病的理解和plopeta在塑造中的作用 长期神经结局。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型疗法发育性脑损伤。