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测序的出现彻底改变了人类疾病中的基因发现，包括 癫痫。在过去的十年中，数百个基因与癫痫有关，揭示了多样性的多样性 这种疾病可能会出现问题的生物学机制。但是，我们确定新基因的速度 现在，参与癫痫病的人现在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 对于早期发作，家族性和难治性癫痫病的患者，外显子组测序已成为标准实践。 将基因测试迅速同化为临床护理，导致了遗传变异的数量激增 不确定的意义（VU），尤其是错义VU的发生。这些VU被分配给 致病性和良性之间的不确定频谱，这使遗传顾问的解释复杂化， 临床医生，患者和家庭，以及对进一步测试的需求进行评估。在这里，我们提出一个中心 没有墙壁，标题为癫痫多层面变体预测（EPIMVP），跨越5个机构和 合并遗传学家，临床医生，计算生物学家，神经科学家，干细​​胞生物学家的专业知识， 具有合作出版物的良好记录的药理学家和电生理学家和电生理学家 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 模块化，高度集成的平台方法，以加速功能，药理， 遗传变异的神经元网络和全动物的后果与一系列临床癫痫有关 类型。我们将研究非离子通道，通常与癫痫有关的非受体基因，并且涉及 在不同的生物过程中。我们的最终目标是设计一个有效的测试实验平台 与癫痫有关的基因中VU的致病性，并产生计算模型（Epipred） 预测变体是致病性或良性的可能性。这项工作对于追求小说至关重要 治疗和个性化医学的希望。该中心的整体里程碑是：1。评估 与癫痫和选择候选者相关的基因进行分析，对数据进行建模和分析所有项目数据 为了开发Epipred的迭代机器学习模型，以对涉及的基因中的变体进行分类 癫痫。 2。使用培养基的体外方法测试选定的VUS。 3。在人类中测试选定的VUS 使用诱导多能干细胞方法的皮质神经元或人脑机形。 4。测试选定的VUS 在临床前体内模型中。预期结果是：1。为 临床医生可以区分与癫痫有关的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。提供重新分类 Clinvar/Clingen中的VUS，并制定将功能读数纳入ACMG的新准则 标准; 4。告知新型治疗剂的未来发展以治疗癫痫。