Cell Type-specific Alternative Splicing Controls Cerebral Cortical Development

细胞类型特异性选择性剪接控制大脑皮层发育

基本信息

批准号：
9766364
负责人：
Xiaochang Zhang
金额：
$ 16.24万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766364
关键词：
Affect Alternative Splicing Architecture Area Boston Brain Brain Diseases Cell Differentiation process Cell Proliferation Cell division Cell physiology Cells Cerebral cortex Cerebrum Childhood Collaborations Complex Computer Simulation Cytoskeleton Data Development Developmental Biology Disease Epilepsy Exons FLNA gene Fluorescence-Activated Cell Sorting Genes Genetic Genetic Transcription Genomics Goals Human Human Genetics Human Genome Individual Knowledge Laboratories Lead Maps Mediating Mental Health Mentors Mentorship Microcephaly Molecular Biology Morphology Mus Mutation Neocortex Nervous System Physiology Neurons Ontology Organism Pathogenicity Pediatric Hospitals Phylogenetic Analysis Physiological Plants Poison Protein Isoforms Proteins RNA Splicing RNA-Binding Proteins Radial Regulation Research Research Personnel Research Training Resources Role Scientist Social Interaction Structure Tertiary Protein Structure Testing Thinking Ventricular autism spectrum disorder autistic brain malformation career cell type collaborative environment developmental neurobiology exome sequencing genetic variant genome-wide genome-wide analysis in vivo instructor mRNA Decay mRNA Precursor medical schools migration multidisciplinary nerve stem cell neurogenesis ninein progenitor programs protein expression public health relevance screening skills skills training transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The human genome contains fewer genes than many seemingly simpler organisms, but humans-especially the human brains-create remarkable protein diversity by alternative pre-mRNA splicing. Dysregulations of alternative splicing networks have been repeatedly found in autistic brains, indicating critical roles of alternative splicing in human mental health. However, it's unclear when and how the human brain acquires complex alternative splicing during development, and our current knowledge lacks a systematic understanding of how the regulation of alternative splicing relates to developmental human brain disorders. A major gap is the lack of a direct comparison of differentially spliced exons between early human neural progenitors and differentiated neurons in development. In this project, Dr. Zhang will combine fluorescence activated cell sorting, RNA sequencing and multidisciplinary functional approaches to test the hypothesis that cell type-specific alternative splicing executes an important layer of control on cerebral cortical development. Specifically, this proposal aims to: 1] Identify genome-wide alternatively spliced exons between cortical neural progenitors and neurons in mice and humans, 2] Investigate the functional impact of alternatively spliced exons, and 3] Identify mutations that cause aberrant alternative splicing and developmental human brain disorders. Dr. Xiaochang Zhang is an Instructor at the Boston Children's Hospital (BCH) and Harvard Medical School, and his proposed 4-year mentored career plan will be performed in the laboratory of Dr. Christopher A. Walsh in the Division of Genetics and Genomics at BCH. Dr. Zhang's background is in molecular and developmental biology, and his long-term career goal is to become an independent investigator with expertise in alternative splicing mediated regulation of cerebral cortex development and human brain disorders. Under the mentorship of Dr. Walsh, a world leading expert in the fields of human cerebral cortical development and disorders, Dr. Zhang has developed a research and training platform that will allow him to acquire the experimental skills and knowledge necessary to be productive in both a mentored and independent setting. To accomplish this, Dr. Zhang will take advantage of the expertise and resources in human genetics and developmental neurobiology of the Walsh lab, acquire additional skills and training in relevant research areas, and establish collaboration with a team of experts. The plan is ideally carried out in the Walsh lab at BCH, given its distinguished record for training research scientists in a rich and collaborative environment.

描述（由适用提供）：人类基因组所包含的基因比许多看似简单的生物少，但人类尤其是人类大脑创造的显着蛋白质多样性。在加速的大脑中反复发现了替代剪接网络的失调，表明替代剪接在人类心理健康中的关键作用。但是，目前尚不清楚人脑在发育过程中何时以及如何获得复杂的替代剪接，而我们当前的知识缺乏对如何调节替代剪接关系与发育性人脑疾病的调节的系统性理解。一个主要的差距是缺乏对早期人神经源性器和发育中分化神经元之间不同剪接外显子的直接比较。在这个项目中，张博士将结合荧光激活的细胞分选，RNA测序和多学科功能方法，以检验以下假设：细胞类型特异性替代剪接对大脑皮质发育执行重要的控制层。具体而言，该提案的目的是：1]确定全基因组的剪接外显子在小鼠和人类中的皮质神经元祖细胞和神经元之间的剪接外显子，2] [2]研究剪接外显子的功能影响，3]识别引起异常的替代性剪接和发育性人类脑部疾病的突变。张张博士是波士顿儿童医院（BCH）和哈佛医学院的讲师，他提议的4年修订职业计划将在克里斯托弗·A·沃尔什（Christopher A. Walsh）博士在BCH的遗传学和基因组学部门进行。张博士的背景是分子和发育生物学，他的长期职业目标是成为具有替代剪接介导的大脑皮层发育和人脑疾病的替代剪接调节的专业知识的独立研究者。在沃尔什博士的心态下，沃尔什博士是人类脑皮质发育和疾病领域的全球领先专家，张博士开发了一个研究和培训平台，使他能够获得在心态和独立环境中提高生产力所必需的实验技能和知识。为此，张博士将利用沃尔什实验室的人类遗传学和发展神经生物学的专业知识和资源，在相关研究领域获得其他技能和培训，并与专家团队建立合作。鉴于其杰出记录在富裕和协作的环境中培训研究科学家。