Biology of developmental encephalopathies presenting with infantile spasms

描述（由申请人提供）：候选人在儿科，医学遗传学和儿童神经学方面接受过充分的培训，并且这K08将允许保护时间用于巩固技能和建立他作为神经遗传学独立研究员的职业生涯。候选人的近期职业目标是整合表型分析，分子遗传学和计算机科学技能，并建立一个研究实验室，成为下一代基因组测序技术和生物信息学之间的桥梁。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。这些目标包括确定新疾病治疗的靶点。环境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。UW长期致力于卓越的医学研究，包括基因组科学系的世界级资源。研究拟议的项目解决婴儿痉挛-一个重要的原因，神经系统疾病的儿童人口，并为新的治疗是非常需要的。我们相信，最好的新疗法将出现时，发病机制的理解。在这项提案中，我们扩大了我们的小组和其他人的证据，腹侧前脑发育和突触功能的异常占ISS的发病机制，通过设计实验，将尖端的基因组学与新的生物信息学方法相结合。我们希望通过一种新的定量表型分析技术来改善婴儿痉挛症的临床分类。我们希望能确定婴儿痉挛症的几个新的遗传原因，并将这些基因与发病机制的途径联系起来，以便在未来开发疾病特异性治疗方法时采取行动。最后，我们将部署一个公开的基于网络的工具，这将有助于诊断，咨询和未来的治疗选择这些疾病。

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.