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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：
10038676
负责人：
Philip Michael Boone
金额：
$ 19.75万
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/10038676
关键词：
3-Dimensional Address Boston Bruck-de Lange syndrome 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 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 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 structural genomics 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.

这份申请提出了一项为期五年的有指导的研究和培训经验，将为菲利普博士做好准备博恩将成为医学神经遗传学、基因组学和疾病建模领域的领先者。候选人拥有贝勒医学院分子和人类遗传学博士学位，曾就读于贝勒医学院基因组结构变异与孟德尔病与詹姆斯·卢普斯基博士。他现在正在完成住院医师培训。在波士顿儿童医院(BCH)攻读博士后期间接受儿科学和临床遗传学培训在马萨诸塞州综合医院(MGH)和布罗德研究所接受Michael Talkowski博士的培训。Dr。布恩的职业目标是成为一名内科科学家，并推进对遗传病患者的护理。该项目将极大地推进这些目标，并促进他的独立研究的基础性发现计划，因为他试图描绘一种新的神经遗传性疾病：基因组组织障碍。这类新兴的基因组疾病涉及编码调节3D的成分的突变染色体的组织。这项工作将阐明突变的分子和表型后果这些基因。具体地说，布恩博士建议：1)使用患者衍生的和 CRISPR产生的IPSC和神经谱系细胞系；2)表征3D基因组的变化(通过Hi-C) 和转录组(通过RNA-seq)，以及人类表型(通过考试和病史)；以及3)尝试通过这个网络中基因的CRISPRA/I纠正细胞模型中的这些缺陷。这项工作将改善对这些疾病的诊断和了解，并为靶向治疗奠定基础。它还将生成关于基因组的空间组织及其所服务的调控目的的基本知识。职业发展计划包括体外神经发育疾病建模、设计和培训功能基因组实验的分析和队列的建立。应聘者将学到所有必要的技能独立研究生涯所需的，包括监督实习生和工作人员，负责任的行为研究、拨款撰写、科学交流和实验室管理。他的主要导师迈克尔博士 Talkowski是麻省理工学院神经病学副教授和布罗德研究所的成员。Dr。 Talkowski是统计、计算和功能基因组学方面的经验丰富的导师和公认的专家。他的合作导师古塞拉博士是一位著名的分子遗传学家，在疾病建模方面拥有丰富的经验。和分子机制。导师委员会还包括基因组组织方面的不同专业知识和神经元功能(Leonid Mirny和Kristen Brennand博士)，临床表型(Angela Lin博士)，以及遗传咨询(黛安·卢森特)Boone博士因此获得了前沿的独特汇聚麻省理工学院、哈佛大学、麻省理工学院和博德研究所的基因组学培训环境，以及杰出的医生- 在麻省理工学院和波士顿大学接受科学家培训。布恩博士、他的导师和他们的机构都完全致力于此他的目标是成为一名独立的内科医生、科学家和临床神经遗传学领域的领导者。