权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MECHANISMS OF RESISTANCE TO EXCITOTOXIC CELL DEATH

抵抗兴奋性毒性细胞死亡的机制

基本信息

批准号：
8402817
负责人：
PAULA E SCHAUWECKER
金额：
$ 33.51万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8402817
关键词：
Antiepileptogenic Bioinformatics Brain Injuries C57BL/6 Mouse Candidate Disease Gene Cell Death Chromosome Mapping Chromosomes, Human, Pair 18 Code Complex Congenic Mice Congenic Strain Convulsions Critical Pathways DNA Databases Development Disease Epilepsy Excitatory Neurotoxins Exclusion Exhibits Exons FVB Mouse FVB/N Mouse Functional disorder Funding Gene Expression Gene Expression Profile Genes Genetic Genetic Complementation Test Genetic Predisposition to Disease Genetic Variation Genome Genome Scan Genomics Genotype Grant Hippocampus (Brain)Housing Human Hypoxia Inbred Strains Mice Kainic Acid Link Maps Methods Modeling Modification Molecular Molecular Analysis Molecular Genetics Molecular Profiling Monitor Mouse Strains Mus Mutant Strains Mice Neurodegenerative Disorders Neurologic Neurons Partial Epilepsies Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Play Predisposition Quantitative Trait Loci RNA Splicing Recovery Recurrence Resistance Resolution Role Seizures Stroke Structural Protein Susceptibility Gene Technology Testing Therapeutic Intervention Time Tissues Transcript Transgenic Mice Transgenic Organisms Variant base candidate identification comparative congenic design excitotoxicity gain of function gene interaction genome sequencing in vivo insight mouse genome mouse model new therapeutic target overexpression prevent programs prospective public health relevance research study resistance mechanism response standard care stem stressor trait

项目摘要

DESCRIPTION (provided by applicant): This application is a direct continuation of our previous grant directed at the genetic mapping of QTL controlling seizure-induced cell death susceptibility in the C57BL/6J and FVB/NJ mouse inbred strains, which differ markedly in their susceptibility to seizure-induced cell death. During the initial funding cycle of this program, we identified 3 susceptibility loci for this complex trait (Sicd1-3) through outcross to C57BL/6J and FVB/NJ mice. In the most recent funding cycle, these loci have been confirmed using reciprocal congenic strains and using interval-specific congenic strains, we have successfully narrowed down our Sicd1 locus to a 3.66 Mb interval. In this application, we propose to use the established congenic strains to: 1) identify quantitative trait genes for Sicd1 and determine if allelic differences in our candidate gene in Sicd1 can control seizure-induced cell death susceptibility in mice; 2) to define and characterize the role of specific candidate genes for the Sicd2 susceptibility locus using exon expression profiling; and 3) to investigate the epistatic interaction between Sicd1 and Sicd2 QTLs influencing susceptibility to seizure-induced cell death. In Aim 1, we will identify prospective candidate genes for the Sicd1 locus and determine whether differences in expression of our candidate gene can result in differential susceptibility to seizure-induced cell death by making several different types of transgenic mice. In Aim 2, we will use existing congenic strains or mice from new, highly informative crosses to further localize and identify the genes responsible for mapping to Sicd2 by recombinational methods combined with transcriptome analysis. Lastly, in Aim 3, we will determine if loci from Sicd1 and from Sicd2 act in a complementary fashion to alter susceptibility to seizure-induced cell death. Taken together, these experiments will elucidate pathways critical for the survival of hippocampal neurons in epilepsy and aid in the identification of candidate seizure-induced cell death modifier genes in the mouse. An understanding of the molecular pathophysiology of this disease is essential to the rational design of therapeutic interventions. As well, the characterization of cell death pathways in epilepsy may provide insights into mechanisms involved in other neurodegenerative disorders in which excitotoxicity plays a central role.

描述(申请人提供)：这项申请是我们之前针对控制癫痫诱导细胞死亡易感性的QTL的基因图谱的直接延续，C57BL/6J和FVB/NJ小鼠近交系在对癫痫诱导细胞死亡的易感性方面存在显著差异。在该项目最初的资助周期中，我们通过与C57BL/6J和FVB/NJ小鼠的异交，确定了这一复杂性状(SICd1-3)的3个易感基因座。在最近的资金周期中，使用相互的同源菌株和区间特异的同源菌株确认了这些基因座，我们成功地将我们的SICd1基因座缩小到3.66 Mb的区间。在这一应用中，我们建议使用已建立的同源菌株来：1)识别SICd1的数量性状基因，并确定我们的候选基因SICd1中的等位基因差异是否可以控制小鼠癫痫诱导的细胞死亡易感性；2)利用外显子表达谱来确定和表征SICD2易感基因的特定候选基因的作用；以及3)研究SICd1和SICD2之间影响癫痫诱导细胞死亡易感性的上位性相互作用。在目标1中，我们将确定SICd1基因座的潜在候选基因，并通过制作几种不同类型的转基因小鼠来确定候选基因的表达差异是否会导致癫痫诱导的细胞死亡的不同易感性。在目标2中，我们将使用现有的同源品系或来自新的高信息量杂交的小鼠，通过重组方法结合转录组分析来进一步定位和鉴定负责定位到SICD2的基因。最后，在目标3中，我们将确定来自SICd1和SICD2的基因座是否以互补的方式改变对癫痫诱导的细胞死亡的易感性。综上所述，这些实验将阐明癫痫中海马神经元存活的关键途径，并有助于识别小鼠癫痫诱导的细胞死亡修饰基因。了解这种疾病的分子病理生理学对于合理设计治疗干预措施是必不可少的。此外，癫痫细胞死亡途径的特征可能为其他神经退行性疾病的机制提供见解，其中兴奋性毒性在其中发挥核心作用。