Defining the Disorders of Genome Organization

定义基因组组织紊乱

• 批准号: 10631082
• 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
• 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/10631082
• 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; Gene Dosage; Gene Duplication; Gene Expression; Gene Mutation; Gene Structure; General Hospitals; Genes; Genetic Counseling; Genetic Diseases; Genetic Transcription; Genome; Genomic medicine; Genomics; Goals; Grant; Health; Hi-C; Human; Human Genetics; In Vitro; Institution; Knowledge; Learning; Massachusetts; Medical; Medical Genetics; Medicine; Mendelian disorder; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Conformation; Molecular Genetics; Mutate; Mutation; Neurodevelopmental Disorder; Neurologic; Neurology; Neuronal Differentiation; Neurons; Organizational Change; Pathogenesis; Patient Care; Patients; Pediatric Hospitals; Pediatrics; Phenotype; Physicians; Population Genetics; Proteins; Reading; Recording of previous events; Regulatory Element; Research; Residencies; Role; Scientist; Therapeutic; Time; Training; Variant; Work; Writing; career; career development; cellular engineering; chromosome conformation capture; clinical phenotype; cohesin; cohort; college; combinatorial; design; 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; mutant; nerve stem cell; nervous system disorder; neural; neurogenetics; post-doctoral training; programs; responsible research conduct; skills; stoichiometry; targeted treatment; three dimensional structure; transcriptome; transcriptome sequencing; transcriptomics

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.

该申请提出了一个为期五年的指导研究和培训经验，将准备菲利普博士 布恩将成为医学神经遗传学、基因组学和疾病建模领域的领导者。候选 拥有贝勒医学院分子和人类遗传学的医学博士和博士学位， 基因组结构变异和孟德尔氏病。他现在正在完成住院实习 在波士顿儿童医院（BCH）接受儿科和临床遗传学培训，同时攻读博士后 在马萨诸塞州总医院（MGH）和布罗德研究所接受Michael Talkowski博士的培训。博士 布恩的职业目标是成为一名医生科学家，并促进对遗传病患者的护理。 这个项目将大大推进这些目标，并促进他的独立研究的基础发现 他试图描述一种新的神经遗传性疾病：基因组组织紊乱。 这类新出现的基因组疾病涉及编码调节3D代谢的组分的突变。 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。具体来说，Boone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基因组的改变（通过Hi-C） 和转录组（通过RNA-seq），以及人类表型（通过考试和历史）;和3）试图 通过该网络中基因的CRISPRa/i来纠正细胞模型中的这些缺陷。这项工作将改善 诊断和了解这些疾病，并为靶向治疗奠定基础。也会产生 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 功能基因组实验分析和队列构建。候选人将学习所有必要的技能 独立的研究生涯所需的，包括监督学员和工作人员，负责任的行为， 研究，资助写作，科学交流和实验室管理。他的主要导师迈克尔博士 Talkowski是MGH神经病学副教授，也是Broad研究所的研究所成员。博士 Talkowski是一位经验丰富的导师和公认的统计，计算和功能基因组学专家。 他的共同导师Gusella博士是一位著名的分子遗传学家，在疾病建模方面具有丰富的经验 和分子机制。指导委员会还包括基因组组织方面的各种专业知识 和神经元功能（Leonid Mirny和Kristen Brennett博士），临床表型（Angela Lin博士），以及 遗传咨询（Diane Lucente）。布恩博士因此有机会获得独特的融合领先的 MGH，哈佛，麻省理工学院和布罗德研究所的基因组学培训环境，以及杰出的医生- 在MGH和BCH接受科学家培训。布恩博士，他的导师，和他们的机构完全致力于这一点 他的目标是成为一名独立的医生-科学家和临床神经遗传学的领导者。

项目成果

A cross-disorder dosage sensitivity map of the human genome.

• DOI: 10.1016/j.cell.2022.06.036
• 发表时间: 2022-08-04
• 期刊: CELL
• 影响因子: 64.5
• 作者: Collins, Ryan L.;Glessner, Joseph T.;Porcu, Eleonora;Lepamets, Maarja;Brandon, Rhonda;Lauricella, Christopher;Han, Lide;Morley, Theodore;Niestroj, Lisa-Marie;Ulirsch, Jacob;Everett, Selin;Howrigan, Daniel P.;Boone, Philip M.;Fu, Jack;Karczewski, Konrad J.;Kellaris, Georgios;Lowther, Chelsea;Lucente, Diane;Mohajeri, Kiana;Noukas, Margit;Nuttle, Xander;Samocha, Kaitlin E.;Trinh, Mi;Ullah, Farid;Vosa, Urmo;Hurles, Matthew E.;Aradhya, Swaroop;Davis, Erica E.;Finucane, Hilary;Gusella, James F.;Janze, Aura;Katsanis, Nicholas;Matyakhina, Ludmila;Neale, Benjamin M.;Sanders, David;Warren, Stephanie;Hodge, Jennelle C.;Lal, Dennis;Ruderfer, Douglas M.;Meck, Jeanne;Magi, Reedik;Esko, Tonu;Reymond, Alexandre;Kutalik, Zoltan;Hakonarson, Hakon;Sunyaev, Shamil;Brand, Harrison;Talkowski, Michael E.
• 通讯作者: Talkowski, Michael E.