Role of Endocannabinoid System in Seizure Sensitivity in Eclampsia

内源性大麻素系统在子痫癫痫发作敏感性中的作用

基本信息

批准号：
10541023
负责人：
Maria Aisha Jones-Muhammad
金额：
$ 4.14万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541023
关键词：
2-arachidonylglycerol Adolescence Adult Affect Agonist Behavior Binding Brain CNR1 gene Cannabinoids Consensus Data Development Eclampsia Electroencephalography Electrophysiology (science)Endocannabinoids Endocrinology Enzymes Epilepsy Epileptogenesis Exhibits Exposure to Female Fetal Development Goals Grant High Pressure Liquid Chromatography Hippocampus (Brain)Hypertension Immunofluorescence Immunologic Impairment Institution Interview Investigation Ligands Manuscripts Mass Spectrum Analysis Maternal Mortality Measures Mentors Mission Modeling Morbidity - disease rate Mothers Mus Neurodevelopmental Disorder Neurons Neurosciences Research Patients Pentylenetetrazole Perfusion Phase Play Postdoctoral Fellow Postpartum Period Pre-Clinical Model Pre-Eclampsia Predisposition Pregnancy Pregnant Women Public Health Publications Rattus Research Research Project Grants Rodent Role Scientist Seizures Severities Sex Differences Social Behavior Stains Testing TimeLine Training United States National Institutes of Health Uterus Western Blotting Woman Work adolescent offspring anandamide antagonist base career career development clinically relevant disability endogenous cannabinoid system excitatory neuron fetal fetal marijuana exposure in utero infancy inhibitory neuron innovation insight interest male maternal marijuana use mortality neurodevelopment new therapeutic target novel offspring post-doctoral training pregnancy disorder pressure prevent programs research and development rimonabant sex sham surgery skills success therapeutic target tissue processing

项目摘要

Project Summary Preeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia, when the mother displays novel seizures. The mechanisms that cause some preeclampsia patients to advance to eclampsia are unknown. The long-term goals are to identify therapeutic targets to prevent seizures in pregnancy and preeclampsia and to pursue a career as an academic scientist. The overall objectives of this application are to: 1) identify whether the endocannabinoid system is involved in increased seizure sensitivity in preclinical model of eclampsia, and 2) provide me the additional training to establish a successful career as an academic scientist. The central hypothesis is that changes in cannabinoid receptor 1 (CB1R) activity is impaired following reduced utero-placental perfusion (RUPP) and that impaired CB1R activation increases seizure severity. The rationale for this project is that the rat RUPP model showed increased seizure susceptibility; however, the contributing factors are not fully known. Additionally, seizures occur when brain activity is not effectively modulated and the endocannabinoid system has been shown to modulate neuronal activity and play a significant role in seizure activity. Our preliminary work shows abnormal expression of enzymes important for endocannabinoid system activity in a mouse RUPP model. Because these enzymes play an important role in modulating CB1R activity, it is possible that the RUPP interferes with the endocannabinoid system’s ability to modulate neuronal activity and thus increases sensitivity to seizures. Aim 1 will determine whether RUPP impairs CB1R activity and whether modulating CB1R activity increases seizure severity following RUPP. My postdoctoral plans in Aim 2 focus on the offspring and will determine whether disrupting the endocannabinoid system during pregnancy leads to sex-specific differences in epilepsy in the adolescent offspring. This application is innovative because it combines a clinically-relevant preclinical model of eclampsia with a well-established neuronal modulator, the endocannabinoids, thus having the potential to identify a novel therapeutic target. This grant will also allow for the continued career development and success of a very promising neuroscientist.

项目概要先兆子痫是一种妊娠期高血压疾病，当母亲显示出导致一些先兆子痫患者进展为新的癫痫发作的机制。子痫尚不清楚，长期目标是确定预防的治疗目标。怀孕和先兆子痫中的癫痫发作，并追求学术科学家的职业生涯。本申请的总体目标是：1) 确定内源性大麻素系统是否参与子痫临床前模型中癫痫敏感性的增加，2）为我提供额外的培训，以建立作为学术科学家的成功职业生涯。假设大麻素受体 1 (CB1R) 活性的变化在减少后受到损害子宫胎盘灌注 (RUPP) 和 CB1R 激活受损会增加癫痫发作的严重程度。该项目的基本原理是大鼠 RUPP 模型显示出癫痫易感性增加；然而，影响因素尚不完全清楚。活性未得到有效调节，内源性大麻素系统已被证明可以调节我们的初步工作表明，神经活动在癫痫活动中发挥着重要作用。对小鼠内源性大麻素系统活性重要的酶的异常表达由于这些酶在调节 CB1R 活性中发挥着重要作用，因此 RUPP 模型。 RUPP 可能会干扰内源性大麻素系统调节神经元的能力活动，从而增加对癫痫发作的敏感性，目标 1 将确定 RUPP 是否会损害。 CB1R 活性以及调节 CB1R 活性是否会增加 RUPP 后癫痫发作的严重程度。我在“目标 2”中的博士后计划重点关注后代，并将确定是否会扰乱怀孕期间的内源性大麻素系统导致癫痫的性别特异性差异该应用程序具有创新性，因为它结合了临床相关的内容。使用成熟的神经元调节剂内源性大麻素的子痫临床前模型，因此有可能确定一个新的治疗靶点。这笔赠款也将允许一位非常有前途的神经科学家的持续职业发展和成功。