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.

项目摘要/摘要该提议着重于人类造血的遗传确定剂，特别是发展造血祖细胞（HPC）及其前体的。增强有很大的兴趣培养的诱导多能干细胞（IPSC）的体外HPC产生，因为这将支持研究和发展许多基于血细胞的疗法。更好地了解可能改善体外血细胞产量，我使用计算建模来分析血液特质基因组范围协会研究（GWAS）数据。我确定并验证了肌动蛋白1是通常约束的基因 HPC的体外产生及其内皮前体细胞。在这笔赠款的目标1中，我将确定 Tropomyosin 1使用明确定义的体外IPSC来调节HPC前体的发展的机制文化模型。在AIM 2中，我将定义使用使用HPC生物学调节HPC生物学的其他基因和遗传机制完整的统计遗传学方法的新型适应。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物理科学家寻求制定研究计划，调查调节的遗传机制造血。我在细胞和分子血液学，儿科培训中完成了MD和博士学位，目前，我正在接受新生儿和围产医学的研究金培训第三年费城医院（CHOP）。拟议的研究将在本杰明的心态下进行 Voight博士，复杂人类遗传学领域的领导者； Stella Chou，医学博士，IPSC衍生的领导者造血和输血医学；以及IPSC操纵的领导者Deborah French，博士，造血培养和血细胞生物学。此外，我得到了一个咨询委员会的支持相关和完整领域中的科学家和身体科学家们共同支持多个K-雄伟的学员。我已经获得了机构的全部支持，并将从中受益卓越的教学培训，广泛的资源和核心设施以及世界一流的精神训练在这个奖项期间，CHOP和宾夕法尼亚大学。理想学术培训 K99支持提供的环境将帮助我发展成为独立的技能在此奖项的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使用计算和生化方法来了解遗传的实验室增强血液产生的机制和治疗策略。在这笔赠款中，我将获得严格的数据科学和造血建模的培训。这将扩大我的技能曲目，推动我的过渡到独立性，并增加了我成功争夺R01资金的可能性。