Baboon Model for Genetics of Human Generalized Epilepsy

人类全身性癫痫遗传学的狒狒模型

• 批准号: 7068602
• 负责人: Jeff Williams
• 金额: $ 28.48万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068602
• 关键词: baboons; biotechnology; disease /disorder model; electroencephalography; epilepsy; gene expression; generalized seizures; genetic markers; genetic models; genetic polymorphism; genotype; linkage disequilibriums; linkage mapping; model design /development; statistics /biometry

DESCRIPTION (provided by applicant): We propose to use the large, pedigreed baboon colony at Southwest Foundation for Biomedical Research (SFBR) in San Antonio, TX, to develop the baboon (Papio hamadryas anubis, Papio hamadryas cynocephalus, and their hybrids) as a nonhuman primate model for the genetics of primary generalized epilepsy in humans. Epilepsy is easily studied in the baboon because these animals are highly susceptible to photic stimulation to provoke neuronal discharges and seizures that are sensitive markers of their epileptic syndrome. The baboon is also an ideal animal for development as a genetic model, because baboon and human share many genetic, anatomical, biochemical, and physiological features. The evolutionary proximity of baboon and human, and the high degree of conservation of gene order between these species, imply that genetic factors identified in the baboon genome will be directly relevant to the genetic situation in the human. Candidate genes identified in the baboon are therefore likely to be relevant for identifying genes in humans. Although the red baboon (Papio hamadryas papio) was first explored more than thirty years ago as a nonhuman primate model of primary generalized epilepsy in humans, and remains one of the best characterized electroclinical animal models for juvenile myoclonic epilepsy, the red baboon cannot be developed further as a genetic model. Development of a genetic model requires large samples, and an accurate knowledge of the relatedness between individuals, in order to separate genetic and environmental sources of variation. Neither of these requirements can be met using the red baboon, however. We will therefore use the large, pedigreed baboon colony at SFBR. Nearly 1500 baboons are members of a single pedigree. About 1000 of these baboons have already been genotyped at 370 or more polymorphic human DNA microsatellite marker loci, and a baboon linkage map is available for genetic linkage analysis. Using these resources we will identify genes that significantly affect variation in the clinical and electroencephalographic features of epilepsy in baboons and are therefore likely to be relevant in human epilepsy. Identification of genes involved in the epilepsy syndrome will implicate specific physiological and biochemical pathways that can be targeted for intervention, and potentially contribute to improvements in existing treatments for epilepsy and the development of novel therapies.

描述(由申请人提供)：我们建议使用位于德克萨斯州圣安东尼奥的西南生物医学研究基金会(SFBR)的大型家系狒狒群体来开发狒狒(Papio hamadryas Anubis，Papio hamadryas cynocephalus及其杂交)，作为人类原发全面性癫痫遗传学的非人类灵长类动物模型。在狒狒身上很容易研究癫痫，因为这些动物对光刺激非常敏感，可以激发神经元放电和癫痫发作，而这些都是它们癫痫综合征的敏感标志。它也是一种理想的遗传模型动物，因为它和人类有许多共同的遗传、解剖、生化和生理特征。狒狒与人类在进化上的相似性，以及这些物种之间基因序列的高度保守性，意味着在狒狒基因组中发现的遗传因素将与人类的遗传状况直接相关。因此，在狒狒中发现的候选基因很可能与识别人类基因有关。尽管30多年前作为人类原发全身性癫痫的非人类灵长类动物模型首次被发现，并一直是青少年肌阵挛癫痫的电临床动物模型之一，但作为一种遗传模型，红狒狒不能进一步发展。开发遗传模型需要大量样本，并对个体之间的关联性有准确的了解，以便分离遗传和环境变异来源。然而，这两个要求都不能用红狒狒来满足。因此，我们将使用SFBR的大型纯种狒狒聚居地。近1500只狒狒是同一系谱的成员。其中约1000只已在370个或更多的人类DNA微卫星标记座位上进行了基因分型，并提供了用于遗传连锁分析的狒狒连锁图谱。利用这些资源，我们将识别显着影响狒狒癫痫临床和脑电特征变异的基因，因此很可能与人类癫痫相关。癫痫综合征相关基因的识别将涉及特定的生理和生化途径，可作为干预的靶点，并可能有助于改进现有的癫痫治疗方法和开发新的治疗方法。