Sex-specific development of seizure activity following endocannabinoid system manipulation in the fetal brain

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Maria Aisha Jones-Muhammad
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $77,859
Funding agency: National Institute of Neurological Disorders and Stroke

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.

Terms: <12-20 years old><21+ years old><Adolescence><Adult><Adult Human><Affect><Agonist><Ammon Horn><Behavior><Binding><Brain><Brain Nervous System><CB1><CB1 Receptor><CB1R><CNR1 gene><Cannabinoid Receptor CB1><Cannabinoids><Common Rat Strains><Consensus><Cornu Ammonis><Data><Developing fetus><Development><Development and Research><Differences between sexes><Differs between sexes><EEG><EPH Gestosis><Eclampsia><Electroencephalogram><Electroencephalography><Electrophysiology><Electrophysiology (science)><Encephalon><Endocannabinoids><Endocrinology><Endogenous Cannabinoids><Enzyme Gene><Enzymes><Epilepsy><Epileptic Seizures><Epileptics><Epileptogenesis><Exhibits><Exposure to><Female><Fetal Development><Gestation><Goals><Grant><HPLC><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Hippocampus><Hypertension><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><Impairment><Institution><Interview><Investigation><Leptazole><Ligands><Manuscripts><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maternal Mortality><Maternal cannabis use><Measures><Mentors><Metabolism and Endocrinology><Mice><Mice Mammals><Mission><Modeling><Molecular Interaction><Morbidity><Morbidity - disease rate><Mothers><Murine><Mus><N arachidonoyl 2 hydroxyethylamide><N-arachidonoylethanolamine><NIH><National Institutes of Health><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Neurophysiology / Electrophysiology><Neurosciences Research><Patients><Pentamethylenetetrazole><Pentetrazole><Pentylenetetrazol><Pentylenetetrazole><Perfusion><Phase><Play><Postdoc><Postdoctoral Fellow><Postpartum Period><Pre-Clinical Model><Pre-Eclampsia><Preclinical Models><Predisposition><Preeclampsia><Pregnancy><Pregnancy Toxemias><Pregnant Women><Proteinuria-Edema-Hypertension Gestosis><Public Health><Publications><R & D><R&D><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Research><Research Associate><Research Grants><Research Project Grants><Research Projects><Rodent><Rodentia><Rodents Mammals><Role><Scientific Publication><Scientist><Seizure Disorder><Seizures><Severities><Sex Differences><Sexual differences><Social Behavior><Staining method><Stains><Susceptibility><Testing><Training><United States National Institutes of Health><Uterus><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Western Blotting><Western Immunoblotting><Woman><Work><acomplia><adolescence (12-20)><adolescent offspring><adulthood><anandamide><antagonism><antagonist><arachidonoyl ethanolamide><arachidonoylethanolamide><arachidonylethanolamide><cannabinoid receptor 1><cannabinoid receptor type 1><cannabinoid type 1><cannabis in utero><career><career development><clinical relevance><clinically relevant><developmental><disability><eCB system><electrophysiological><endocannabinoid system><endogenous cannabinoid system><epilepsia><epileptogenic><excitatory neuron><expectant mother><expecting mother><fetal><fetal cannabis exposure><fetal marijuana exposure><gestational marijuana exposure><high blood pressure><hippocampal><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><in utero><infancy><infantile><inhibitory neuron><innovate><innovation><innovative><insight><interest><male><maternal death><maternal marijuana use><mortality><neurodevelopment><neurodevelopmental disease><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><offspring><post-doc><post-doctoral><post-doctoral trainee><post-doctoral training><post-partum><postdoctoral training><pre-eclamptic><pregnancy disorder><pregnancy toxemia/hypertension><pregnant mothers><prenatal cannabis exposure><prenatal marijuana exposure><prenatally exposed to cannabis><prenatally exposed to marijuana><prenatally marijuana exposed><pressure><prevent><preventing><programs><protein blotting><research and development><research associates><rimonabant><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><sham surgery><skills><social role><sociobehavior><sociobehavioral><success><therapeutic target><timeline><tissue processing><womb><zimulti>