Project-004

项目-004

• 批准号: 10670387
• 负责人: Lori L. Isom
• 金额: $ 21.6万
• 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/10670387
• 关键词: Acceleration; Animals; Benign; Biodiversity; Biological; Biological Process; Brain; Cells; Classification; ClinVar; Clinical; Computer Models; DNA sequencing; Data; Development; Disease; Epilepsy; Experimental Models; Family; Future; Genes; Goals; Grant; Guidelines; Human; In Vitro; Institution; International; Intervention; Intractable Epilepsy; Ion Channel; Ligands; Needs Assessment; Neurons; Organoids; Outcome; Pathogenicity; Pathway interactions; Patient Care; Patients; Pre-Clinical Model; Proteins; Publications; 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; 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测序的出现使人类疾病的基因发现发生了革命性的变化，包括 癫痫。在过去的十年里，数百种基因与癫痫有关，揭示了 在这种疾病中可能出现错误的生物机制。然而，我们识别新基因的速度 参与癫痫的研究现在已经超过了我们研究疾病机制的能力。此外，临床基因小组或 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做法。 这种将基因检测迅速同化到临床护理中的做法，导致了基因变异的数量激增 不确定意义(VU)，特别是错误意义VU的发生。这些VU被分配给 致病和良性之间的光谱不确定，这使得遗传顾问的解释变得复杂， 临床医生、患者和家属，以及对进一步检测的必要性的评估。在这里，我们建议成立一个中心 无墙，名为癫痫多平台变量预测(EpiMVP)，涵盖5个机构和 融合了遗传学家、临床医生、计算生物学家、神经学家、干细胞生物学家的专业知识， 药理学家和电生理学家，他们在合作出版物和 赠款，以及作为国家和国际癫痫组织领导人的地位。EpiMVP将开发一种 模块化、高度集成的平台方法，可加快功能、药理、 与一系列临床癫痫有关的基因变异的神经网络和整个动物后果 类型。我们将研究与癫痫有关的非离子通道、非受体基因。 在各种生物过程中。我们的最终目标是设计一个有效的测试实验平台 癫痫相关基因中VUS的致病性，并生成一个计算模型(EpiPred) 预测变异是致病的或良性的可能性。这部作品在追求小说的过程中至关重要 治疗学和个性化药物的前景。该中心的总体里程碑是：1.评估 与癫痫相关的基因，并选择候选对象进行分析、数据建模和分析所有项目数据 为了开发EpiPred，一种迭代的机器学习模型来分类涉及到的基因的变体 癫痫。2.使用中等吞吐量的体外方法测试选定的VU。3.在人体内测试选定的VU 使用诱导多能干细胞方法的皮质神经元或人脑器官。4.测试选定的VU 在临床前和活体模型中。预期的结果是：1.提供免费的预测工具 临床医生区分癫痫相关基因的致病和良性变异；2.提供 研究特定变体的功能后果的实验模型；3.提供一个重新分类的 ClinVar/Clingen中的VUS，并制定将功能读数纳入ACMG的新指南 标准；4.告知未来治疗癫痫的新疗法的发展。