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Defining the disorders of genome organization

定义基因组组织紊乱

基本信息

批准号：
10417145
负责人：
Philip Michael Boone
金额：
$ 19.76万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417145
关键词：
3-Dimensional Address Boston Bruck-de Lange syndrome CRISPR-mediated transcriptional activation Case Study Cell Line Cell Lineage Cell Nucleus Cell model Cells Chromosome Segregation Chromosome Structures Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communication Complex Congenital Abnormality DNA Defect Development Plans Diagnosis Disease Disease model Doctor of Philosophy Engineering Enrollment Environment Foundations Gene Dosage Gene Duplication Gene Expression Gene Mutation General Hospitals Genes Genetic Counseling Genetic Diseases Genetic Transcription Genome Genomic medicine Genomics Goals Health Hi-C Human Human Genetics In Vitro Institutes Institution Knowledge Lead Learning Massachusetts Medical Medical Genetics Medicine Mendelian disorder Mentors Mentorship Methods Modeling Molecular Molecular Computations Molecular Conformation Molecular Genetics Mutate Mutation Neurologic Neurology Neuronal Differentiation Neurons Organizational Change Pathogenesis Patient Care Patients Pediatric Hospitals Pediatrics Phenotype Physicians Play Population Genetics Proteins Reading Recording of previous events Regulatory Element Research Research Project Grants Research Training Residencies Role Scientist Supervision Therapeutic Time Training Variant Work Writing career career development cellular engineering chromosome conformation capture clinical phenotype cohesin cohort college combinatorial dosage experience experimental study functional genomics gene function gene network genetic analysis human disease improved individual patient induced pluripotent stem cell insight laboratory experience loss of function member meter mid-career faculty model design molecular phenotype mutant nerve stem cell nervous system disorder neurogenetics post-doctoral training programs relating to nervous system responsible research conduct skills stoichiometry targeted treatment three dimensional structure transcriptome transcriptome sequencing transcriptomics

项目摘要

This application proposes a five-year mentored research and training experience that will prepare Dr. Philip Boone to be a leader in the fields of medical neurogenetics, genomics, and disease modeling. The candidate has an MD and PhD in Molecular and Human Genetics from Baylor College of Medicine, where he studied genomic structural variation and Mendelian disease with Dr. James Lupski. He is now completing residency training in Pediatrics and Clinical Genetics at Boston Children’s Hospital (BCH) while pursuing postdoctoral training with Dr. Michael Talkowski at Massachusetts General Hospital (MGH) and the Broad Institute. Dr. Boone’s career goal is to become a physician-scientist and to advance care for patients with genetic disease. This project will greatly advance those goals and facilitate foundational discoveries for his independent research program as he seeks to delineate a new class of neurogenetic disease: the disorders of genome organization. This emerging class of genomic disorders involve mutations encoding components that regulate the 3D organization of chromosomes. This work will elucidate the molecular and phenotypic consequences of mutation of these genes. Specifically, Dr. Boone proposes to: 1) model these disorders using patient-derived and CRISPR-generated iPSC and neural lineage cell lines; 2) Characterize alterations to the 3D genome (via Hi-C) and transcriptome (via RNA-seq), as well as the human phenotype (via exams and history); and 3) Attempt to correct these defects in cellular models via CRISPRa/i of genes in this network. The work will improve the diagnosis and understanding of these disorders and lay the groundwork for targeted therapy. It will also generate fundamental knowledge about the spatial organization of the genome and the regulatory purpose it serves. The career development plan includes training in in vitro neurodevelopmental disease modeling, design and analysis of functional genomic experiments, and cohort building. The candidate will learn all the requisite skills needed for an independent research career, including supervising trainees and staff, responsible conduct of research, grant writing, scientific communication, and lab management. His primary mentor, Dr. Michael Talkowski, is Associate Professor of Neurology at MGH and Institute Member at the Broad Institute. Dr. Talkowski is an experienced mentor and recognized expert in statistical, computational, and functional genomics. His co-mentor, Dr. Gusella, is a renowned molecular geneticist with considerable experience in disease modeling and molecular mechanisms. The mentorship committee also includes diverse expertise in genome organization and neuronal function (Drs. Leonid Mirny and Kristen Brennand), clinical phenotyping (Dr. Angela Lin), and genetic counseling (Diane Lucente). Dr. Boone thus has access to the unique convergence of leading-edge genomics training environments at MGH, Harvard, MIT, and the Broad Institute, and remarkable physician- scientist training at MGH and BCH. Dr. Boone, his mentors, and their institutions are fully committed to this proposal and to his goal of becoming an independent physician-scientist and leader in clinical neurogenetics.

这个应用程序提出了一个五年的指导研究和培训经验，将准备博士菲利普