Regulating proliferation and differentiation of erythroid progenitors

调节红系祖细胞的增殖和分化

• 批准号: 10436152
• 负责人: Hojun Li
• 金额: $ 16.52万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436152
• 关键词: Affect; American Society of Hematology; Anemia; Architecture; Automobile Driving; Award; BFU-E; Basic Science; Biology; Biomedical Research; Bone Marrow; Bone marrow failure; Boston; CFU-E; Cell Count; Cell Cycle; Cell Differentiation process; Cell division; Cells; Child; Chromatin; Clinical; Collaborations; Development; Developmental Biology; Diamond-Blackfan anemia; Differentiation Antigens; Disease; Disease model; Ensure; Equilibrium; Erythrocytes; Erythroid; Erythroid Cells; Erythroid Progenitor Cells; Erythropoiesis; Erythropoietin; Failure; Fostering; Functional disorder; GYPA gene; Gene Targeting; Generations; Genes; Glucocorticoid Receptor; Glucocorticoids; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Human; Institutes; Institution; International; MADH2 gene; Malignant Neoplasms; Maps; Marrow; Mediating; Mentors; Molecular; Mus; Output; Patients; Pharmacotherapy; Physicians; Positioning Attribute; Principal Investigator; Production; Proliferating; RNA; Receptor Activation; Receptor Signaling; Research; Research Personnel; Resistance; Science; Scientist; Signal Transduction; Speed; TFRC gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Transcript; Transducers; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Translating; Translations; Work; career development; clinical efficacy; differential expression; erythroid differentiation; follow-up; improved; inhibitor; insight; novel; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; progenitor; research and development; single-cell RNA sequencing; skills; stem cells; success; transcription factor; transcriptome; transcriptomics

PROJECT SUMMARY / ABSTRACT Diamond-Blackfan anemia (DBA) is a unique example of a bone marrow failure disorder that improves with drug treatment. Glucocorticoids increase red blood cell production in most DBA patients, but the underlying mechanism of clinical efficacy was unclear until recently. I identified a phenomenon where mouse burst forming unit-erythroid (BFU-E) cells progress through a continuum of developmental states during transit-amplification; glucocorticoid treatment decreases the degree of developmental progression per cell cycle, resulting in a greater number of transit-amplifying cell divisions before the onset of erythroid terminal differentiation (Developmental Cell, 2019). Conversely, TGFβ treatment of BFU-Es increases rate of developmental progression and decreases overall BFU-E proliferative capacity. My findings defined a novel developmental biology paradigm where rate of progenitor cell developmental progression regulates balance of proliferation and differentiation, and total cellular output. Insights into the mechanisms by which glucocorticoids and TGFβ regulate proliferative capacity remain elusive, and the conclusions from my mouse erythropoiesis studies must be directly tested in human erythropoiesis. I will identify the target genes of glucocorticoid and TGFβ signaling in BFU-Es using nascent transcriptome profiling and chromatin occupancy and architecture profiling. Furthermore, I will use single cell RNA sequencing of normal and DBA patient bone marrow hematopoietic progenitor cells to compare glucocorticoid and TGFβ effects on mouse erythropoiesis and human erythropoiesis. My proposed studies will: (i) contribute broadly to our understanding of pathophysiology and treatment principles in bone marrow failure, (ii) further develop a novel field within developmental biology that arose from my earlier postdoctoral work, and (iii) provide ample opportunities for mechanistic and translational follow-up for my transition to independence. I am a physician-scientist seeking K08 support for mentored research under the guidance of Dr. Harvey Lodish and Dr. Stuart Orkin. This mentored period of 80% research and career development, and 20% clinical time, will ensure I acquire the skills required to become a successful independent principal investigator. Drs. Lodish and Orkin are internationally recognized mentors, together training >200 successful independent investigators; both received the American Society of Hematology Basic Science Mentor Award. My training will occur at two world- class institutions, the Whitehead Institute for Biomedical Research, and the Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Both are rich with opportunities for young scientists to train, pursue highly impactful science, and foster long-lasting collaborations. I will also be guided by a committee of researchers that are all leaders in their fields: Drs. David Bartel (RNA biology), Peter Reddien (developmental biology), and Akiko Shimamura (bone marrow failure). The support of this K08 award will allow me to focus on maturing my research and strengthening my career development during this critical last stage of mentored training. At the conclusion of my award period, I will be optimally positioned for achieving success as an independent physician-scientist.

项目摘要 /摘要 Diamond-Blackfan贫血（DBA）是骨髓衰竭障碍的独特例子，可以通过药物改善 治疗。大多数DBA患者的糖皮质激素增加了红细胞的产生，但基础 直到最近，临床效率的机制还不清楚。我确定了一种现象，其中小鼠爆发形成 单位 - 炎症（BFU-E）细胞在运输过程中通过发育状态的连续发展； 糖皮质激素治疗降低了每个细胞周期的发育进展程度，导致更大 在红细胞终末分化开始之前（发育范围 Cell，2019）。相反，BFU-E的TGFβ治疗增加了发育进展的速度并下降 总体BFU-E增殖能力。我的发现定义了一种新颖的发育生物学范例，其中 祖细胞发育进展调节增殖和分化的平衡，总细胞 输出。洞悉糖皮质激素和TGFβ调节增生剂能力的机制 难以捉摸，我的小鼠红细胞生成研究的结论必须直接在人类中进行测试 红细胞生成。我将使用新生的BFU-E中识别糖皮质激素和TGFβ信号的靶基因 转录组分析和染色质占用和建筑分析。此外，我将使用单个单元格 正常和DBA患者骨髓造血祖细胞的RNA测序以比较 糖皮质激素和TGFβ对小鼠促红细胞生成和人类促红细胞生成的影响。我建议的研究将： （i）对我们对骨髓衰竭病理生理学和治疗原理的理解广泛贡献， （ii）进一步发展了发育生物学中的新领域，这是我较早的博士后工作以及 （iii）为我向独立过渡提供了足够的机械和翻译跟进机会。 我是一个身体科学家，在Harvey Lodish博士的指导下寻求K08支持指导研究的支持 和斯图尔特·奥金（Stuart Orkin）博士。这项修补了80％的研究和职业发展，以及20％的临床时间，将 确保我获得成为成功的独立首席调查员所需的技能。博士。 lodish和 奥金（Orkin）是国际认可的导师，培训> 200个成功的独立研究人员；两个都 获得了美国血液学基础科学导师奖。我的培训将在两个世界中进行 - 班级机构，怀特黑德生物医学研究所和达娜·法伯/波士顿儿童 癌症和血液疾病中心。两者都有丰富的年轻科学家进行训练的机会 有影响力的科学，并促进了长期的合作。我还将受到研究人员委员会的指导 都是他们领域的领导者：Drs。 David Bartel（RNA生物学），Peter Reddien（发展生物学）和Akiko Shimamura（骨髓衰竭）。该K08奖的支持将使我能够专注于成熟我的研究 并在修补培训的最后阶段加强了我的职业发展。结论 在我的奖励期内，我将因取得独立的身体科学家的成功而处于最佳状态。