Biology of developmental encephalopathies presenting with infantile spasms

应聘者描述(由申请人提供)：应聘者受过儿科、医学遗传学和儿童神经学方面的全面培训，这份K08证书将为巩固技能和建立他作为神经遗传学独立研究人员的职业生涯留出有保障的时间。候选人的近期职业目标是整合表型、分子遗传学和计算机科学技能，并建立一个研究实验室，在下一代基因组测序技术和生物信息学之间架起桥梁。长期的职业目标是进一步了解影响美国大量儿童的关键神经发育障碍--癫痫、自闭症和智力残疾。在这些目标中，包括确定新疾病疗法的目标。这项拟议的工作将在西雅图儿童研究所(SCRI)进行，全基因组测序将在华盛顿大学(UW)完成。威斯康星大学长期致力于卓越的医学研究，包括基因组科学部的世界级资源。研究拟议的项目针对婴儿痉挛--这是儿科人群神经系统疾病的一个重要原因，迫切需要新的治疗方法。我们相信，当了解了潜在的发病机制后，最好的新疗法将会出现。在这项提案中，我们通过设计将尖端基因组学与新的生物信息学方法相结合的实验，来扩展我们团队和其他人的证据，即腹侧前脑发育和突触功能异常是ISS发病机制的原因。我们期望通过一种新的定量表型技术来改善以婴儿痉挛为表现的疾病的临床分类。我们希望确定婴儿痉挛的几个新的遗传原因，并将这些基因与致病途径联系起来，以便在未来疾病特异性治疗的开发中发挥作用。最后，我们将部署一个公开可用的基于网络的工具，该工具将有助于这些疾病的诊断、咨询和未来的治疗选择。

DESCRIPTION (provided by applicant): The candidate is fully trained in pediatrics, medical genetics, and child neurology, and this K08 will allow protected time for the consolidation of skills and establishment of his career as an independent researcher in neurogenetics. The candidate's immediate career goals are to integrate phenotyping, molecular genetics, and computer science skills, and establish a research lab the bridges between next-generation genomic sequencing technologies and bioinformatics. Long term career goals are to further the understanding of the key neurodevelopmental disorders affecting large numbers of children in the United States -- epilepsy, autism, and intellectual disability. Inclusive in these goals are th identification of targets for new disease therapies. Environment The proposed work will be performed at the Seattle Children's Research Institute (SCRI), and whole genome sequencing will be completed at the University Of Washington (UW). UW has a longstanding commitment to excellence in medical research, including world-class resources in the Department of Genome Sciences. Research The proposed project addresses infantile spasms - a significant cause of neurologic morbidity in the pediatric population, and for which new therapies are much needed. We believe the best new therapies will arise when underlying mechanisms of pathogenesis are understood. In this proposal we expand on evidence from our group and others that abnormalities of ventral forebrain development and synapse function account for ISS pathogenesis, by designing experiments that integrate cutting-edge genomics with novel bioinformatics approaches. We expect to improve the clinical classification of the disorders presenting with infantile spasms with a new technique of quantitative phenotyping. We expect to identify several new genetic causes of infantile spasms, and to connect those genes to pathways of pathogenesis that can be acted upon in the future development of disease-specific therapies. Finally, we will deploy a publicly available web-based tool that will help in the diagnosis, counseling, and future therapy selection for these disorders.