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.

该申请提出了五年的指导研究和培训经验，这将为菲利普博士做好准备。布恩是医学神经遗传学，基因组学和疾病建模领域的领导者他在惠尔（Whire）贝勒医学院拥有分子和人类遗传学的医学博士学位和博士学位詹姆斯·卢普斯基（James Lupski）博士与基因组结构变异和门德尔病。波士顿儿童医院（BCH）的儿科和临床遗传学培训，同时追求博士后在马萨诸塞州综合医院（MGH）和大型研究所的迈克尔·泰克斯基（Michael Talkowski）培训。布恩的职业目标是成为医师科学家，并为患有遗传疾病的患者提供护理。该项目将极大地促进这些目标，并促进基础基础基础基础，以实现其独立研究他试图描绘基因组组织的新神经基因的计划。这种新兴类别的基因组疾病涉及编码与3D规则的组件的突变染色体的组织。在这些基因中。 CRISPR生成的IPSC和神经谱系细胞系；和转录组（通过RNA-Seq）作为人类表型（通过考试和历史）；通过网络中基因的CRISPRA/I纠正细胞模型中的缺陷。对这些疾病的诊断和理解并进行靶向疗法。关于基因组的空间组织及其服务的常规目的的基本知识。职业发展计划包括在体外神经发育疾病建模，设计和设计方面的培训以及分析功能基因组经验和候选人的队列。独立研究职业所需的需要，包括监督培训和员工，负责任的行为研究，授予写作，科学沟通和实验室管理。 Talkowski是MGH的神经病学副教授，也是Broad Institute的研究所成员。 Talkowski是一位经验丰富的导师，并在统计，计算和功能基因组学中得到认可。他的同事Gusella博士是一位著名的分子Genetixist，在疾病建模方面拥有丰富的经验和分子机制。和神经元功能（Leonid Mirny和Kristen Brennand博士），临床表型（Angela Lin博士）和遗传咨询（Diane Lucente）。 MGH，哈佛，麻省理工学院和广泛研究所的基因组学培训环境，以及出色的医生 - MGH和BCH博士的科学家培训。提议及其目标是否定独立医师科学家和临床神经遗传学领域的领导者。