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（由申请人提供）：此应用是我们以前的赠款的直接延续，该赠款针对C57BL/6J和FVB/NJ小鼠inbred菌株的QTL控制癫痫发作诱导的细胞死亡易感性的遗传图，这在其对塞济兹诱导的细胞死亡的敏感性方面明显不同。在该计划的最初资助周期中，我们通过outsross到C57BL/6J和FVB/NJ小鼠确定了该复杂性状（SICD1-3）的3个敏感性基因座（SICD1-3）。在最近的融资周期中，这些基因座已通过相互的先天性菌株得到证实，并使用间隔特定的先天性菌株证实了这些基因座，我们成功地将SICD1基因座缩小到3.66 MB的间隔。在此应用中，我们建议使用已建立的先天性菌株来：1）确定SICD1的定量性状基因，并确定SICD1中候选基因中的等位基因差异是否可以控制小鼠癫痫发作诱导的细胞性细胞死亡易感性； 2）使用外显子表达分析定义和表征特定候选基因在SICD2易感基因座中的作用； 3）研究SICD1与SICD2 QTL之间的上皮相互作用，从而影响了癫痫发作诱导的细胞死亡的敏感性。在AIM 1中，我们将确定SICD1基因座的前瞻性候选基因，并确定我们候选基因表达的差异是否会通过制造几种不同类型的转基因小鼠来导致对癫痫发作诱导的细胞死亡的敏感性差异。在AIM 2中，我们将使用新的，高度信息丰富的十字架中现有的先天性菌株或小鼠，以进一步定位和识别负责通过重组方法与转录组分析结合使用的基因。最后，在AIM 3中，我们将以互补的方式确定SICD1和SICD2的基因座是否可以改变对癫痫发作诱发的细胞死亡的敏感性。综上所述，这些实验将阐明对癫痫中海马神经元存活至关重要的途径，并有助于鉴定小鼠中候选癫痫发作诱导的细胞死亡修饰剂基因。对这种疾病的分子病理生理学的理解对于治疗干预的合理设计至关重要。同样，癫痫中细胞死亡途径的表征也可以提供对涉及其他神经退行性疾病的机制的见解，在这些机制中，兴奋性毒性起着核心作用。