Defining the Disorders of Genome Organization

定义基因组组织紊乱

基本信息

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
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/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

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.

该申请提出了为期五年的指导研究和培训经验，将为菲利普博士做好准备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。拥有贝勒医学院分子和人类遗传学医学博士和博士学位，他曾就读于此詹姆斯·卢普斯基博士的基因组结构变异和孟德尔病他现在正在完成住院医师实习。在波士顿儿童医院 (BCH) 攻读博士后期间接受儿科和临床遗传学培训在麻省总医院 (MGH) 和布罗德研究所 (Broad Institute) 接受 Michael Talkowski 博士的培训。布恩的职业目标是成为一名医师科学家并促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发现他试图描述一类新的神经遗传疾病：基因组组织紊乱。这一类新兴的基因组疾病涉及编码调节 3D 的组件的突变。这项工作将阐明突变的分子和表型后果。具体来说，布恩博士建议：1）使用源自患者的基因和基因来模拟这些疾病。 CRISPR 生成的 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（通过检查和历史）；3）尝试通过该网络中基因的 CRISPRa/i 纠正细胞模型中的这些缺陷。诊断和了解这些疾病并为靶向治疗奠定基础。有关基因组空间组织及其所服务的调控目的的基础知识。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分析和队列建设候选人将学习所有必要的技能。独立研究生涯所需的，包括监督受训者和工作人员、负责任的行为他的主要导师迈克尔博士。 Talkowski 是麻省总医院神经病学副教授和布罗德研究所成员。 Talkowski 是一位经验丰富的导师，也是统计、计算和功能基因组学领域公认的专家。他的合作导师 Gusella 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 博士和 Kristen Brennand 博士）、临床表型分析（Angela Lin 博士），以及遗传咨询（黛安·卢森特）布恩博士因此获得了独特的前沿融合。麻省总医院、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- MGH 和 BCH 的科学家培训，Boone 博士、他的导师以及他们的机构都全力致力于此。提案以及他成为一名独立的医师科学家和临床神经遗传学领域领导者的目标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.