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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：
8601130
负责人：
PAULA E SCHAUWECKER
金额：
$ 34.38万
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 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8601130
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）：本申请是我们之前资助的直接延续，该资助旨在控制 C57BL/6J 和 FVB/NJ 小鼠近交系中癫痫诱导的细胞死亡易感性的 QTL 的遗传图谱，这两种小鼠对癫痫诱导的细胞死亡的易感性显着不同。在该计划的初始资助周期中，我们通过与 C57BL/6J 和 FVB/NJ 小鼠的异型杂交，确定了这种复杂性状 (Sicd1-3) 的 3 个易感位点。在最近的资助周期中，这些基因座已使用互惠同源菌株和使用区间特异性同源菌株得到确认，我们已成功将 Sicd1 基因座缩小到 3.66 Mb 区间。在本申请中，我们建议使用已建立的同源菌株来：1）鉴定Sicd1的数量性状基因，并确定Sicd1中候选基因的等位基因差异是否可以控制小鼠癫痫发作诱导的细胞死亡易感性； 2) 使用外显子表达谱来定义和表征 Sicd2 易感位点的特定候选基因的作用； 3) 研究 Sicd1 和 Sicd2 QTL 之间的上位相互作用影响癫痫诱导的细胞死亡的易感性。在目标 1 中，我们将鉴定 Sicd1 基因座的潜在候选基因，并通过制备几种不同类型的转基因小鼠来确定候选基因表达的差异是否会导致对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、信息丰富的杂交的小鼠，通过重组方法与转录组分析相结合，进一步定位和鉴定负责映射到 Sicd2 的基因。最后，在目标 3 中，我们将确定 Sicd1 和 Sicd2 的基因座是否以互补的方式发挥作用，以改变癫痫引起的细胞死亡的易感性。总而言之，这些实验将阐明癫痫患者海马神经元存活的关键途径，并有助于鉴定小鼠中候选的癫痫诱导细胞死亡修饰基因。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至关重要。此外，癫痫细胞死亡途径的表征可能有助于深入了解其他神经退行性疾病的机制，其中兴奋性毒性发挥着核心作用。