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

基本信息

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
项目类别：
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

项目摘要

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可能使数以千计的胎儿面临终生危险。每年绝大多数研究都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，即关键胎盘激素的作用。有助于正常的大脑发育，而它们的缺失会导致这样一个关键的胎盘损伤。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。我们的初步实验表明，无论是啮齿类动物还是人类妊娠期，ALLO 主要是由胎盘产生的。研究表明，妊娠期间药理学 ALLO 减少会扰乱皮质-海马回路此外，内源性和外源性 ALLO 还可以促进成熟并改变 GABA 亚基的表达。然而，使用 ALLO 作为围产期治疗剂在多种临床前损伤模型中具有神经保护作用。到目前为止，了解妊娠期 ALLO 的具体来源、生理水平和作用至关重要。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我们已经建立了小鼠模型，其中 ALLO 的产生仅在这些模型首次允许直接胎盘类固醇操作。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）并且存在持久使用我们的新 floxed 小鼠模型抑制胎盘 ALLO 后的功能性神经改变。（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 对以下方面至关重要：1) 皮质生成；2) 长期行为和回路功能； 3) 可能适合围产期治疗的损伤的机制的阐明。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。