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Quantitative Genetic Study of Seizures

癫痫发作的定量遗传学研究

基本信息

批准号：
8549645
负责人：
THOMAS N FERRARO
金额：
$ 3.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549645
关键词：
Address Applications Grants Architecture Behavioral Bioinformatics Biological Brain Diseases Candidate Disease Gene Chemicals Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 15 Chromosomes, Human, Pair 3 Chromosomes, Human, Pair 4 Chromosomes, Human, Pair 5 Chromosomes, Human, Pair 6 Chromosomes, Human, Pair 8 Clinical Research Complex Congenic Mice Congenic Strain Convulsants DNA Development Disease Dissection Distal Electroconvulsive Shock Epilepsy Etiology Funding Genes Genetic Genetic Models Genetic Predisposition to Disease Genetic Research Genetic Variation Genomics Goals Health Human Inbred Strains Mice Kainic Acid Knowledge Laboratories Lead Literature Maps Measures Messenger RNA Modeling Mus Patients Pentylenetetrazole Phenotype Pilocarpine Population Positioning Attribute Predisposition Protein Analysis Proteins Quantitative Genetics Quantitative Trait Loci Recombinants Research Resistance Resolution Risk Sampling Seizures Susceptibility Gene Testing Therapeutic Transgenic Mice Translating Translational Research Translations Variant Work base genetic analysis genetic association improved insight mouse model novel prototype repository success trait

项目摘要

DESCRIPTION (provided by applicant): The studies proposed in this application represent a request to continue characterizing naturally-occurring gene variation that determines seizure susceptibility in mice. The primary model under study involves two common strains of inbred mice that differ robustly with respect to their susceptibility to experimentally-induced seizures, C57BL/6J (B6), which is relatively seizure resistant, and DBA/2J (D2), which is relatively seizure susceptible. Whereas the short term goal of studies in this project is related to the identification of seizure susceptibility genes in mice, the long term goal involves translation of these studies into focused hypotheses and studies involving human patients with epilepsy. Thus, in the past funding period, we used the B6-D2 mouse model to identify Kcnj10 as a putative seizure susceptibility gene underlying the quantitative trait locus (QTL) on distal Chr 1. Upon translation to a clinical study, we showed that KCNJ10 genetic variation in humans is associated with risk for common forms of epilepsy. Importantly, this latter finding was confirmed by an independent laboratory and exists as one of the few replicated epilepsy genetic associations in the literature. Thus the past funding period enabled us to demonstrate "proof of principle" and the overall utility of our translational research strategy. As a result of the success achieved in the dissection and translation of the distal Chr 1 QTL (Szs1) in the B6- D2 model, we have recently (February 2008) submitted a new grant application to study the mechanism of Kcnj10 genetic variation in seizure susceptibility and thus do not propose further study of that gene in this project. Rather, we will focus on analysis of seizure susceptibility QTLs of next highest priority in the B6-D2 model which were also studied in the previous funding period. Thus in Aims 1 and 2 we propose to fine-map and analyze candidate genes in critical QTL intervals on Chr 5 and Chr 15, respectively. This work will include creation of recombinant congenic strains between B6 and D2 mice, determination of seizure susceptibility using well-established paradigms involving maximal electroshock seizure threshold (MEST) and chemical convulsants, bioinformatics and mRNA and protein analysis of candidate genes. Aim 3 will focus on a new genetic model developed in the last funding period involving C57BL/KsJ (Ks) and C57BL/10SnJ (B10S) inbred strains of mice. In this model, we propose to confirm MEST QTLs identified on Chrs 3, 4, 6 and 8 by capturing them in congenic strains which will be created rapidly and in parallel with each other. The extent of the influence of MEST QTLs on seizure susceptibility will be evaluated in those congenic strains in which MEST QTLs are captured by testing them with chemoconvulsants pentylenetetrazol (PTZ), kainic acid (KA) and pilocarpine (PC). QTLs will be prioritized for further dissection based upon the results from all paradigms. The studies proposed in this project will have immediate impact on the field of epilepsy genetics research. Since our laboratory is dedicated to a translational research strategy, results will be used directly to inform clinical studies of patients with epilepsy. We maintain a growing repository of over 1000 DNA samples from patients with epilepsy and use them to investigate candidate genes that are suggested by the mouse studies. Work completed in this project during the past funding period provides "proof of principle" for the utility of this strategy and thus serves as a prototype that we propose to follow for further elucidation of the complex genetic architecture that defines human epilepsy. Ultimately, a better understanding of the biological basis of seizure susceptibility and genetic predisposition to epilepsy will facilitate the development of novel and more effective therapeutic options for patients and may one day lead to a cure for this devastating group of diseases. PUBLIC HEALTH RELEVANCE: This project involves the identification of genes in mice that determine their susceptibility to experimentally- induced seizures. Whereas the short term goal of the project involves the identification of seizure susceptibility genes, the longer term goal is to try to understand how they influence seizure susceptibility. Ultimately, the knowledge gained from these studies on mice will be applied in our laboratory to human patients with epilepsy and thus will have immediate impact on the field of epilepsy genetics research. Since our laboratory is dedicated to a translational research strategy, results from work on mice will be used directly to inform clinical studies. We maintain a repository of over 1000 DNA samples from patients with common forms of epilepsy and we use them to investigate genes that are suggested by our mouse research such as those proposed in this project. Ultimately, a better understanding of the biological basis of seizure susceptibility in mice and genetic predisposition to epilepsy in humans will facilitate the development of novel and more effective therapeutic options for patients with epilepsy and may one day lead to a cure for this devastating group of brain diseases.

描述（由申请人提供）：本申请中提出的研究代表了继续表征决定小鼠癫痫易感性的自然发生的基因变异的请求。研究中的主要模型涉及两种常见的近交系小鼠，它们对实验诱导的癫痫发作的敏感性明显不同，C57 BL/6 J（B6）相对具有癫痫发作抗性，DBA/2 J（D2）相对具有癫痫发作易感性。虽然该项目研究的短期目标与识别小鼠癫痫易感基因有关，但长期目标涉及将这些研究转化为重点假设和涉及癫痫患者的研究。因此，在过去的资助期间，我们使用B6-D2小鼠模型，以确定Kcnj 10作为一个假定的癫痫发作易感基因的数量性状位点（QTL）的远端Chr 1。在转化为临床研究后，我们发现人类的KCNJ 10遗传变异与常见形式的癫痫风险相关。重要的是，后一项发现得到了独立实验室的证实，并且是文献中少数几个重复的癫痫遗传关联之一。因此，过去的资助期使我们能够证明“原则证明”和我们的转化研究战略的整体效用。由于在B6- D2模型中远端Chr 1 QTL（Szs 1）的解剖和翻译中取得的成功，我们最近（2008年2月）提交了一份新的资助申请，以研究Kcnj 10遗传变异在癫痫发作易感性中的机制，因此不建议在本项目中进一步研究该基因。相反，我们将重点分析B6-D2模型中次高优先级的癫痫易感性QTL，这些QTL也在前一个资助期进行了研究。因此，在目标1和2中，我们建议分别在Chr 5和Chr 15上的关键QTL间隔中精细定位和分析候选基因。这项工作将包括创建B6和D2小鼠之间的重组同源株，使用完善的范例，包括最大电休克癫痫发作阈值（MEST）和化学惊厥剂，生物信息学和候选基因的mRNA和蛋白质分析癫痫发作易感性的测定。目标3将侧重于在上一个资助期开发的一种新的遗传模型，涉及C57 BL/KsJ（Ks）和C57 BL/10 SnJ（B10 S）近交系小鼠。在该模型中，我们建议通过在同源株系中捕获它们来确认在Chrs 3、4、6和8上鉴定的MEST QTL，所述同源株系将快速且彼此平行地产生。MEST QTL对癫痫易感性的影响程度将在那些通过用化学惊厥剂戊四氮（PTZ）、红藻氨酸（KA）和毛果芸香碱（PC）测试而捕获MEST QTL的同源菌株中进行评估。将基于来自所有范例的结果对QTL进行优先排序以用于进一步剖析。该项目提出的研究将对癫痫遗传学研究领域产生直接影响。由于我们的实验室致力于转化研究策略，因此结果将直接用于癫痫患者的临床研究。我们保持了一个不断增长的超过1000个癫痫患者DNA样本的库，并使用它们来研究小鼠研究所建议的候选基因。在过去的资助期间完成的工作在这个项目中提供了“原则证明”的效用，这种策略，从而作为一个原型，我们建议遵循进一步阐明复杂的遗传结构，定义人类癫痫。最终，更好地了解癫痫发作易感性和癫痫遗传易感性的生物学基础将有助于为患者开发新的和更有效的治疗方案，并可能有一天治愈这组毁灭性的疾病。公共卫生相关性：这个项目涉及到在老鼠身上识别基因，这些基因决定了它们对实验诱导的癫痫发作的易感性。虽然该项目的短期目标涉及癫痫易感基因的识别，但长期目标是试图了解它们如何影响癫痫易感性。最终，从这些小鼠研究中获得的知识将在我们的实验室中应用于人类癫痫患者，从而对癫痫遗传学研究领域产生直接影响。由于我们的实验室致力于转化研究策略，因此小鼠研究的结果将直接用于临床研究。我们维护了一个来自常见癫痫患者的1000多个DNA样本的储存库，我们用它们来研究我们的小鼠研究所提出的基因，例如本项目中提出的基因。最终，更好地了解小鼠癫痫易感性的生物学基础和人类癫痫的遗传易感性将有助于为癫痫患者开发新的更有效的治疗方案，并可能有一天治愈这种毁灭性的脑部疾病。