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.

项目总结/摘要 这项建议的重点是人类造血的遗传决定因素，特别是发展 造血祖细胞（HPCs）及其前体细胞。有相当大的兴趣增加在 从培养的诱导多能干细胞（iPSC）中体外生产HPC，因为这将支持研究和 许多基于血细胞的疗法的发展。为了更好地了解基因和基因组位点， 为了提高体外血细胞产量，我使用计算机建模来分析全基因组的血液性状 关联研究（GWAS）数据。我鉴定并验证了原肌球蛋白1是一种通常抑制 HPC及其内皮前体细胞的体外产生。在本补助金的目标1中，我将确定 原肌球蛋白1通过明确的体外iPSC调控HPC前体发育的机制 文化模式在目标2中，我将定义其他基因和遗传机制，调节HPC生物学， 互补统计遗传学方法的新适应。 拟议的五年培训计划概述了我作为学术儿科研究生涯的发展 一位寻求开发一项研究计划的医生科学家，该计划调查调节 造血我完成了细胞和分子血液学的医学博士和博士学位，儿科住院医师培训， 我目前在儿童医院接受新生儿和围产期医学研究员培训的第三年， 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博士，iPSC衍生的领导者 造血和输血医学;以及Deborah French博士，iPSC操纵的领导者， 造血培养和血细胞生物学。此外，我还得到一个咨询委员会的支持， 相关和互补领域的科学家和医生科学家，他们共同支持 多名K奖学员我已经得到了我所在机构的全力支持，并将受益于 卓越的教学培训，广泛的资源和核心设施，以及世界一流的导师， CHOP和宾夕法尼亚大学在本奖项期间。在理想的学术培训 K99支持提供的环境将帮助我发展成为独立工作者所需的技能。 在该奖项的R00阶段研究造血遗传学的医生科学家。 我的目标是经营一个实验室，利用计算和生物化学的方法来了解遗传 增强血液生成的机制和治疗策略。在这份资助中，我将获得严格的 数据科学和造血建模培训。这将扩大我的技能库，推动我的 过渡到独立，并增加我成功竞争R01资金的可能性。