Project-005

项目-005

基本信息

  • 批准号:
    10455563
  • 负责人:
  • 金额:
    $ 6.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

The advent of next generation DNA sequencing has revolutionized gene discovery in human diseases, including epilepsy. Hundreds of genes have been implicated in epilepsy in the last decade, revealing the diversity of biological mechanisms that can go awry in this disorder. However, the rate at which we are identifying new genes involved in epilepsy is now outpacing our ability to study disease mechanisms. Moreover, clinical gene panel or exome sequencing has become standard practice for patients with early-onset, familial, and refractory epilepsies. This rapid assimilation of genetic testing into clinical care has led to a surge in the number of genetic variants of uncertain significance (VUS), particularly the occurrence of missense VUS. These VUS are assigned to an indeterminate spectrum between pathogenic and benign, which complicate interpretation for genetic counselors, clinicians, patients and families, as well as assessment of the need for further testing. Here we propose a Center without Walls, entitled Epilepsy Multiplatform Variant Prediction (EpiMVP), spanning 5 institutions and incorporating expertise from geneticists, clinicians, computational biologists, neuroscientists, stem cell biologists, pharmacologists and electrophysiologists who have a proven track record of collaborative publications and grants, as well as stature as leaders of national and international epilepsy organizations. EpiMVP will develop a modular, highly integrated platform approach to accelerate determination of the functional, pharmacological, neuronal network and whole animal consequences of genetic variants implicated in a range of clinical epilepsy types. We will study non-ion-channel, non-receptor genes commonly implicated in epilepsy, and that are involved in diverse biological processes. Our ultimate goals are to devise an effective experimental platform for testing the pathogenicity of VUS in genes implicated in epilepsy and to generate a computational model (EpiPred) that predicts the likelihood that a variant is pathogenic or benign. This work is crucial in the pursuit of novel therapeutics and the promise of personalized medicine. The overall milestones of the Center are: 1. Evaluate genes associated with epilepsy and select candidates for analysis, model data for, and analyze all project data for development of EpiPred an iterative machine learning model to classify variants in genes implicated in epilepsy. 2. Test selected VUS using medium throughput, in vitro approaches. 3. Test selected VUS in human cortical neurons or human brain organoids using induced pluripotent stem cell approaches. 4. Test selected VUS in pre-clinical, in vivo models. The expected outcomes are: 1. Provide a freely available prediction tool for clinicians to differentiate between pathogenic and benign variants for genes implicated in epilepsy; 2. Provide experimental models to study the functional consequences of specific variants; 3. Provide a reclassification of VUS in ClinVar/ClinGen and to develop new guidelines for incorporating functional readouts into the ACMG criteria; 4. Inform the future development of novel therapeutics to treat epilepsy.
下一代DNA测序的出现彻底改变了人类疾病的基因发现,包括 癫痫在过去的十年中,数百个基因与癫痫有关,揭示了癫痫的多样性。 在这种疾病中可能出错的生物机制。然而,我们发现新基因的速度 参与癫痫的研究已经超过了我们研究疾病机制的能力。此外,临床基因面板或 外显子组测序已经成为早发性、家族性和难治性癫痫患者的标准实践。 这种基因检测迅速融入临床护理的做法导致了遗传变异数量的激增, 不确定意义(VUS),特别是错义VUS的发生。这些VUS被分配给 致病和良性之间的不确定谱,这使遗传咨询师的解释复杂化, 临床医生、患者和家属,以及对进一步检测需求的评估。在这里,我们提出一个中心 无墙,题为癫痫多平台变异预测(EpiMVP),跨越5个机构, 结合遗传学家,临床医生,计算生物学家,神经科学家,干细胞生物学家, 药理学家和电生理学家,他们有合作出版物的良好记录, 赠款,以及作为国家和国际癫痫组织领导人的地位。EpiMVP将开发一个 模块化、高度集成的平台方法,以加速功能性、药理学 一系列临床癫痫中涉及的遗传变异的神经元网络和整个动物后果 类型我们将研究非离子通道,非受体基因通常牵连癫痫,并参与 在不同的生物过程中。我们的最终目标是设计一个有效的实验平台, VUS在与癫痫有关的基因中的致病性,并产生一个计算模型(EpiPred), 预测变异是致病性还是良性的可能性。这部作品在追求小说方面至关重要 治疗学和个性化医疗的前景。该中心的总体里程碑是:1。评价 与癫痫相关的基因,并选择候选人进行分析,建模数据,并分析所有项目数据 为了开发EpiPred,一种迭代机器学习模型,用于对涉及以下方面的基因中的变异进行分类: 癫痫2.使用中等通量的体外方法测试选定的VUS。3.在人体中测试选定的VUS 皮质神经元或人脑类器官。4.测试选定的VUS 在临床前,体内模型中。预期的结果是:1。提供免费的预测工具, 临床医生区分与癫痫有关的基因的致病性和良性变异; 2.提供 研究特定变体的功能后果的实验模型; 3.提供重新分类 ClinVar/ClinGen中的VUS,并制定将功能读数纳入ACMG的新指南 标准; 4.告知治疗癫痫的新疗法的未来发展。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Lori L. Isom其他文献

I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain?
I. 钠通道 β 亚基的细胞和分子生物学:对疼痛的治疗意义?
Na+ channel subunits and Ig domains
钠离子通道亚单位和免疫球蛋白结构域
  • DOI:
    10.1038/383307b0
  • 发表时间:
    1996-09-26
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Lori L. Isom;William A. Catterall
  • 通讯作者:
    William A. Catterall
Modulation of Kv1 Voltage-Gated Potassium Channels by Sodium Channel Beta Subunits
  • DOI:
    10.1016/j.bpj.2011.11.3733
  • 发表时间:
    2012-01-31
  • 期刊:
  • 影响因子:
  • 作者:
    Hai M. Nguyen;Jeffrey D. Calhoun;Lori L. Isom;Alan L. Goldin;George K. Chandy
  • 通讯作者:
    George K. Chandy
Dramatic Improvement in Seizures With Phenytoin Treatment in an Individual With Refractory Epilepsy and a <em>SCN1B</em> Variant
  • DOI:
    10.1016/j.pediatrneurol.2020.03.012
  • 发表时间:
    2020-07-01
  • 期刊:
  • 影响因子:
  • 作者:
    Louis T. Dang;Shane C. Quinonez;Bridget R. Becka;Lori L. Isom;Sucheta M. Joshi
  • 通讯作者:
    Sucheta M. Joshi
Ontology accelerates few-shot learning capability of large language model: A study in extraction of drug efficacy in a rare pediatric epilepsy
本体论加速大型语言模型的少样本学习能力:一项关于罕见儿童癫痫药物疗效提取的研究
  • DOI:
    10.1016/j.ijmedinf.2025.105942
  • 发表时间:
    2025-09-01
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Pedram Golnari;Katrina Prantzalos;Veronica Hood;Mary Anne Meskis;Lori L. Isom;Karen Wilcox;Jack M. Parent;Dennis Lal;Samden D. Lhatoo;Howard P. Goodkin;Elaine C. Wirrell;Kelly G. Knupp;Manisha Patel;Jeffrey A. Loeb;Joseph E. Sullivan;Lauren Harte-Hargrove;Brandy E. Fureman;Jeffrey Buchhalter;Satya S. Sahoo
  • 通讯作者:
    Satya S. Sahoo

Lori L. Isom的其他文献

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{{ truncateString('Lori L. Isom', 18)}}的其他基金

Development and Validation of a Transgenic Rabbit Model of Dravet Syndrome
Dravet 综合征转基因兔模型的开发和验证
  • 批准号:
    10574719
  • 财政年份:
    2023
  • 资助金额:
    $ 6.58万
  • 项目类别:
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
  • 批准号:
    10616678
  • 财政年份:
    2021
  • 资助金额:
    $ 6.58万
  • 项目类别:
Interdepartmental Training in Pharmacological Sciences
药理学科学跨部门培训
  • 批准号:
    10397983
  • 财政年份:
    2021
  • 资助金额:
    $ 6.58万
  • 项目类别:
Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy
癫痫猝死的心脏机制
  • 批准号:
    10454393
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Epilepsy Multiplatform Variant Prediction (EpiMVP) - Admin Core
癫痫多平台变异预测 (EpiMVP) - 管理核心
  • 批准号:
    10670354
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Project-004
项目-004
  • 批准号:
    10455562
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Development of a Rabbit Model of SCN1A-linked Dravet Syndrome
SCN1A 相关 Dravet 综合征兔模型的开发
  • 批准号:
    10062010
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Cardiac Mechanisms of Sudden Unexpected Death in Epilepsy
癫痫猝死的心脏机制
  • 批准号:
    10661021
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Project-005
项目-005
  • 批准号:
    10265447
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:
Project-005
项目-005
  • 批准号:
    10670389
  • 财政年份:
    2020
  • 资助金额:
    $ 6.58万
  • 项目类别:

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