Determining genetic mechanisms that drive in vitro hematopoiesis

确定驱动体外造血的遗传机制

• 批准号: 10453654
• 负责人: Christopher Stephen Thom
• 金额: $ 16.74万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453654
• 关键词: Actins; Address; Advisory Committees; Aging; Award; Biochemical; Bioinformatics; Biology; Blood; Blood Cells; Blood Platelets; Blood Transfusion; CRISPR/Cas technology; Candidate Disease Gene; Cell Line; Cell Therapy; Cell model; Cells; Cellular biology; Childhood; Chromatin; Communicable Diseases; Complex; Computer Models; Core Facility; Data; Data Science; Development; Disease Outbreaks; Doctor of Philosophy; Endothelial Cells; Endothelium; Environment; Epigenetic Process; Erythrocytes; Fellowship; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Determinism; Genetic study; Goals; Grant; Healthcare Systems; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Human Genetics; In Vitro; Institution; Isoantibodies; K-Series Research Career Programs; Knock-out; Laboratories; Link; Maps; Megakaryocytes; Mentorship; Modeling; Molecular; Molecular and Cellular Biology; Neonatal; Other Genetics; Pathway interactions; Patients; Pediatric Hospitals; Pediatrics; Pennsylvania; Phase; Philadelphia; Physicians; Production; Quantitative Trait Loci; Reagent; Research; Research Support; Residencies; Resources; Role; Running; Scientist; Secure; Single Nucleotide Polymorphism; Site; Source; Stem Cell Development; Surface; System; Techniques; Therapeutic; Training; Training Programs; Transfusion; Translational Research; Tropomyosin; United States National Institutes of Health; Universities; Validation; Variant; White Blood Cell Count procedure; base; blood product; career; causal variant; cell type; clinically relevant; genetic approach; genetic testing; genome wide association study; genome-wide; genomic data; genomic locus; hematopoietic differentiation; human model; improved; induced pluripotent stem cell; induced pluripotent stem cell technology; interest; knock-down; molecular hematology; multidisciplinary; next generation sequencing; novel; overexpression; perinatal medicine; precursor cell; predictive modeling; programs; research and development; single-cell RNA sequencing; skills; small hairpin RNA; stem cells; success; trait; transfusion medicine

PROJECT SUMMARY/ABSTRACT This proposal focuses on genetic determinants underlying human hematopoiesis, specifically the development of hematopoietic progenitor cells (HPCs) and their precursors. There is considerable interest in augmenting in vitro HPC production from cultured induced pluripotent stem cells (iPSCs), as this would support research and development of many blood cell-based therapies. To better understand genes and genomic loci that might improve in vitro blood cell yields, I used computational modeling to analyze blood trait genome wide association study (GWAS) data. I identified and validated Tropomyosin 1 as a gene that normally constrains in vitro production of HPCs and their endothelial precursor cells. In Aim 1 of this grant, I will determine mechanisms by which Tropomyosin 1 regulates HPC precursor development using well-defined in vitro iPSC culture models. In Aim 2, I will define other genes and genetic mechanisms that regulate HPC biology using novel adaptations of complementary statistical genetics approaches. The proposed five-year training program outlines development of my research career as an academic pediatric physician-scientist seeking to develop a research program investigating genetic mechanisms that regulate hematopoiesis. I completed an MD and PhD in cell and molecular hematology, pediatrics residency training, and am currently in my third year of fellowship training in neonatal and perinatal medicine at the Children’s Hospital of Philadelphia (CHOP). The proposed research will be carried out under the mentorship of Benjamin Voight, PhD, a leader in the field of complex human genetics; Stella Chou, MD, a leader in iPSC-derived hematopoiesis and transfusion medicine; and Deborah French, PhD, a leader in iPSC manipulation, hematopoietic culture, and blood cell biology. In addition, I am supported by an advisory committee composed of scientists and physician-scientists in relevant and complementary fields, who have together supported multiple K-award trainees. I have secured complete support from my institution, and will benefit from exceptional didactic training, extensive resources and core facilities, and world-class mentorship available at CHOP and the University of Pennsylvania for the duration of this award period. Training in an ideal academic environment, afforded by K99 support, will help me develop the skills required to become an independent physician-scientist studying hematopoiesis genetics during the R00 phase of this award. My goal is to run a laboratory that uses computational and biochemical approaches to understand genetic mechanisms and therapeutic strategies that enhance blood production. In this grant, I will obtain rigorous training in data science and hematopoiesis modeling. This will expand my repertoire of skills, propel my transition to independence, and increase my likelihood of success competing for R01 funding.

项目摘要/摘要 这项建议侧重于人类造血的遗传决定因素，特别是发育 造血祖细胞及其前体细胞。有相当大的兴趣扩大在 体外培养的诱导多能干细胞(IPSCs)产生HPC，因为这将支持研究和 许多基于血细胞的疗法的发展。为了更好地了解可能 提高体外血细胞产量，我使用计算建模来分析全基因组的血液性状 联合研究(GWAS)数据。我鉴定并验证了原肌球蛋白1是一种基因，它通常限制在 体外培养造血祖细胞及其内皮前体细胞。在这笔赠款的目标1中，我将决定 原肌球蛋白1利用体外明确的IPSC调控HPC前体发育的机制 文化典范。在目标2中，我将定义其他基因和遗传机制，这些基因和遗传机制使用 互补统计遗传学方法的新改编。 拟议的五年培训计划概述了我作为一名儿科学术人员的研究生涯的发展。 内科医生-科学家，寻求开发一项研究计划，研究调节 造血术。我完成了细胞和分子血液学的医学博士学位，儿科住院医师培训， 我目前正在儿童医院接受新生儿和围产期医学方面的第三年团契培训 费城医院(CHOP)。拟议的研究将在本杰明的指导下进行 Voight博士，复杂人类遗传学领域的领导者；Stella Chou，医学博士，iPSC衍生领域的领导者 造血和输血医学；以及iPSC操作的领先者黛博拉·弗伦奇博士， 造血培养和血细胞生物学。此外，我还得到了一个咨询委员会的支持，该委员会由 由相关和互补领域的科学家和内科科学家组成，他们共同支持 多名K奖实习生。我已经获得了我的机构的全力支持，并将受益于 卓越的教学培训、广泛的资源和核心设施以及世界级的指导，请访问 CHOP和宾夕法尼亚大学在此授权期内。培养理想的学术人才 K99支持提供的环境将帮助我培养成为独立人员所需的技能 在该奖项的R00阶段研究造血遗传学的内科医生和科学家。 我的目标是运营一个使用计算和生物化学方法来了解基因的实验室 增强血液生成的机制和治疗策略。在这笔赠款中，我将获得严格的 数据科学和造血模型方面的培训。这将扩大我的技能储备，推动我的 过渡到独立，并增加我竞争R01资金的成功可能性。