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Pediatric seizures: role of IP3R Ca2+ release channels

小儿癫痫发作：IP3R Ca2 释放通道的作用

基本信息

批准号：
10195841
负责人：
Prosper N'Gouemo
金额：
$ 12.89万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195841
关键词：
Pediatric seizures role IP3R Ca2+

项目摘要

Alcohol withdrawal following prenatal alcohol exposure (PAE) is frequently associated with generalized tonic- clonic seizures (GTCS) and epilepsy in infants and young children. Our long-term goal is to understand how Ca2+ signaling can be used to prevent and treat PAE-related seizures. We recently developed a rat model of GTCSs following alcohol withdrawal after PAE, in which increased GTCS prevalence was observed in P7-P28 and P7- P35 female and male postpartum rats, respectively. In this model, neonate inferior colliculus (IC) neurons exhibit: i) increased Ca2+-dependent firing in postnatal stage and ii) increased Ca2+ release from inositol triphosphate receptor (IP3R) Ca2+ pools is increased in the IC in both pre-and postnatal stages. The experiments proposed here are designed to determine the precise contribution of three IP3R subtypes—IP3R1, IP3R2 and IP3R3 to GTCS susceptibility following alcohol withdrawal after a single PAE episode during the 2nd trimester, proving specific targets for developing new specific approaches. Our objective in this proposal is to investigate the role of Ca2+ release from intracellular IP3R Ca2+ pools in IC neuronal hyperexcitability in response to alcohol withdrawal after PAE in the 2nd trimester of gestation. Our working hypothesis is that alcohol withdrawal following PAE during the 2nd trimester PAE upregulates IP3R Ca2+ pools resulting in elevated Ca2+ release, which in turn contribute to IC neuronal hyperexcitability and increased seizure susceptibility. To test our central hypothesis, our experiments will combine Ca2+ imaging with electrophysiology, molecular genetics, and pharmacology. The research proposal seeks to address four questions: i) how does Ca2+ release from intracellular IP3R Ca2+ pools is altered in IC neurons of postpartum P35 female and male rats? ii) how does inhibition of Ca2+ release from IP3R Ca2+ pools suppressed IC neuronal firing in postpartum P35 female and rats prenatally exposed to alcohol at E18? iii) how does alcohol withdrawal following PAE alter IP3R mRNA and protein expression in the IC of postpartum PAE P35 female and male postpartum rats? and iv) how does inhibition of IP3R in the IC suppresses GTCS in postpartum PAE P28 and P35, respectively. Overall Impact: Other than generic anticonvulsant medication, there is no specific therapy for pediatric seizures related to alcohol withdrawal after PAE. By revealing how aberrant IP3R-gated Ca2+ release mechanisms contribute to pediatric seizures following alcohol withdrawal after PAE, we will increase understanding of these channels as potential therapeutic targets for managing PAE-related seizures.

产前酒精暴露（PAE）后的酒精戒断通常与全身性强直相关- 阵挛性发作（GTCS）和婴儿和幼儿癫痫。我们的长期目标是了解Ca 2 + 信号传导可用于预防和治疗PAE相关的癫痫发作。我们最近开发了一种大鼠GTCS模型在PAE后酒精戒断后，在P7-P28和P7-P28中观察到GTCS患病率增加， P35雌性和雄性产后大鼠。在该模型中，新生下丘（IC）神经元表现出： i）在出生后阶段增加的Ca 2+依赖性放电和ii）从三磷酸肌醇增加的Ca 2+释放在出生前和出生后两个阶段，IC中的IP 3R Ca 2+池增加。提出的实验本文旨在确定三种IP 3R亚型-IP 3R 1，IP 3R 2和IP 3R 3对妊娠中期单次PAE发作后戒酒后的GTCS易感性，证明制定新的具体办法的具体目标。我们在本提案中的目标是调查在酒精引起的下丘神经元过度兴奋中从胞内IP 3R Ca ~（2+）池释放Ca ~（2+）的研究妊娠第二个三个月PAE后停药。我们的工作假设是酒精戒断后孕中期的PAE上调IP 3R Ca 2+池，导致Ca 2+释放升高，这反过来导致IC神经元过度兴奋和癫痫发作易感性增加。为了验证我们的核心假设，我们的实验将联合收割机钙离子成像与电生理学、分子遗传学和药理学相结合。的一项研究计划试图解决四个问题：i）Ca 2+如何从细胞内IP 3R Ca 2+池中释放在产后P35雌性和雄性大鼠IC神经元中的改变？（2）如何抑制Ca 2+的释放 IP 3R Ca 2+池抑制产后P35雌性和产前暴露于酒精的大鼠的IC神经元放电在E18？iii）PAE后的酒精戒断如何改变IP 3R mRNA和蛋白在IC中的表达，产后PAE P35雌性和雄性产后大鼠？以及iv）IC中IP 3R的抑制如何抑制产后PAE的GTCS分别为P28和P35。总体影响：非通用抗惊厥药在药物治疗方面，对于PAE后与酒精戒断相关的儿科癫痫发作没有特异性治疗。通过揭示了异常IP 3R门控Ca 2+释放机制如何导致儿童酒精后癫痫发作我们将增加对这些通道作为潜在治疗靶点的理解，管理PAE相关癫痫发作。