Determining genetic mechanisms that drive in vitro hematopoiesis

确定驱动体外造血的遗传机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案重点关注人类造血的遗传决定因素，特别是发育人们对增强造血祖细胞（HPC）及其前体细胞非常感兴趣。从培养的诱导多能干细胞 (iPSC) 进行体外 HPC 生产，因为这将支持研究和开发许多基于血细胞的疗法，以更好地了解可能的基因和基因组位点。为了提高体外血细胞产量，我使用计算模型来分析全基因组的血液特征我确定并验证了原肌球蛋白 1 作为通常限制的基因。 HPC 及其内皮前体细胞的体外生产在本次资助的目标 1 中，我将确定。原肌球蛋白 1 使用明确的体外 iPSC 调节 HPC 前体发育的机制在目标 2 中，我将使用调节 HPC 生物学的其他基因和遗传机制。补充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寻求开发一个研究项目来调查调节遗传机制的医生科学家我完成了细胞和分子血液学、儿科住院医师培训的医学博士和博士学位，目前我正在儿童医院接受新生儿和围产期医学进修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 医学博士，iPSC 衍生领域的领导者造血和输血医学；以及 iPSC 操作领域的领导者 Deborah French 博士，此外，我还得到了一个顾问委员会的支持。相关和互补领域的科学家和医师科学家共同支持我已经获得了我所在机构的全力支持，并将受益于多名 K 奖学员。卓越的教学培训、广泛的资源和核心设施以及世界一流的指导 CHOP 和宾夕法尼亚大学在此奖励期间进行理想的学术培训。由 K99 支持提供的环境将帮助我培养成为独立人士所需的技能在该奖项的 R00 阶段研究造血遗传学的医师科学家。我的目标是运营一个实验室，使用计算和生化方法来理解遗传在这笔资助中，我将获得严格的促进血液生成的机制和治疗策略。数据科学和造血建模方面的培训这将扩展我的技能，推动我的发展。过渡到独立，并增加我成功竞争 R01 资金的可能性。