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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：
9305160
负责人：
Xiaochang Zhang
金额：
$ 9.48万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305160
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 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.