Epilepsy Multiplatform Variant Prediction (EpiMVP)

癫痫多平台变异预测 (EpiMVP)

• 批准号: 10670343
• 负责人: Lori L. Isom
• 金额: $ 238.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10670343
• 关键词: Acceleration; Animals; Benign; Biodiversity; Biological; Biological Process; Brain; Cell Line; Cells; Classification; ClinVar; Clinical; Communication; Communities; Computer Models; DNA sequencing; Data; Data Analyses; Development; Disease; Epilepsy; Experimental Models; Family; Future; Genes; Goals; Grant; Guidelines; Human; In Vitro; Institution; International; Intervention; Intractable Epilepsy; Ion Channel; Ligands; Machine Learning; Molecular Biology; Needs Assessment; Neurons; Organoids; Outcome; Pathogenicity; Pathway interactions; Patient Care; Patients; Pre-Clinical Model; Proteins; Publications; Services; System; Testing; Variant; Work; candidate selection; clinical care; data modeling; disease mechanisms study; early onset; exome sequencing; gene discovery; gene panel; genetic counselor; genetic testing; genetic variant; human disease; human pluripotent stem cell; in vivo Model; induced pluripotent stem cell; innovation; machine learning model; new therapeutic target; next generation; novel strategies; novel therapeutics; personalized medicine; pharmacologic; pre-clinical; predictive modeling; predictive tools; receptor; stem cells; tool; variant of unknown significance

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包括癫痫在内的人类疾病中的基因发现。在过去的十年中，数百个基因与癫痫有关，揭示了这种疾病中可能出现问题的生物学机制的多样性。但是，我们确定与癫痫有关的新基因的速度现在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成为早期，家族性和难治性癫痫患者的标准实践。基因检测在临床护理中的快速同化导致了不确定意义的遗传变异数量的激增（VUS），尤其是错义VUS的发生。这些VU被分配到致病性和良性之间的不确定范围，这使遗传顾问，临床医生，患者和家庭的解释变得复杂，并评估了进一步测试的需求。在这里，我们提出了一个没有墙壁的中心，标题为癫痫互多平面变体预测（EPIMVP），跨越了5个机构，并纳入了遗传学家，临床医生，计算生物学家，神经科学家，干细​​胞生物学家，药物学家，药物学家和电生理学家的专业知识，他们拥有可靠的出版物记录记录。作为国家和国际癫痫组织的领导人的赠款以及身材。 EPIMVP将开发一种模块化的，高度集成的平台方法，以加速对功能，药理，神经元网络的确定，以及与一系列临床癫痫类型有关的遗传变异的全部动物后果。我们将研究非离子通道，通常与癫痫有关的非受体基因，并且与多种生物学过程有关。我们的最终目标是设计一个有效的实验平台，用于测试与癫痫有关的基因中VU的致病性，并生成一个计算模型（EPIPRED），以预测变体具有致病性或良性的可能性。这项工作对于追求新颖的治疗学和个性化医学的希望至关重要。该中心的整体里程碑是：1。评估与癫痫相关的基因，并选择候选者进行分析，建模数据并分析所有项目数据，以开发Epipred的迭代机器学习模型，以对癫痫中涉及的基因中的变体进行分类。 2。使用培养基的体外方法测试选定的VUS。 3。使用诱导的多能干细胞方法测试人类皮质神经元或人脑器官中选定的VU。 4。测试在临床前的体内模型中选定的VU。预期的结果是：1。为临床医生提供了一种自由获得的预测工具，可以区分与癫痫有关的基因的致病和良性变异。 2。提供实验模型来研究特定变体的功能后果； 3。提供Clinvar/Clingen中VUS的重新分类，并制定将功能读数纳入ACMG标准的新准则； 4。告知新型治疗剂的未来发展以治疗癫痫。

项目成果

Protocol for selecting single human pluripotent stem cells using a modified micropipetter.

• DOI: 10.1016/j.xpro.2023.102629
• 发表时间: 2023-12-15
• 期刊: STAR PROTOCOLS
• 作者: Mojica-Perez, Sandra P.;Stokes, Kyle;Jaklic, Daniel C.;Jahagirdar, Sheetal;Uhler, Michael;Parent, Jack M.;Niu, Wei
• 通讯作者: Niu, Wei