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.

项目概要/摘要 戴蒙德-布莱克范贫血 (DBA) 是骨髓衰竭性疾病的一个独特例子，可通过药物改善 糖皮质激素会增加大多数 DBA 患者的红细胞生成，但其根本原因是。 直到最近我发现了一种小鼠爆裂形成的现象，其临床疗效的机制尚不清楚。 红系单位 (BFU-E) 细胞在转运扩增过程中经历一系列发育状态； 糖皮质激素治疗降低了每个细胞周期的发育进展程度，从而导致更大的 红系终末分化开始之前的转运放大细胞分裂次数（发育 Cell，2019），BFU-E 的 TGFβ 处理可提高发育进展速度并降低。 我的研究结果定义了一种新的发育生物学范式，其中 BFU-E 的增殖能力。 祖细胞发育进程调节增殖和分化的平衡，以及总细胞 对糖皮质激素和 TGFβ 调节增殖能力的机制的见解仍然存在。 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身上进行测试 我将使用新生的 BFU-E 来识别糖皮质激素和 TGFβ 信号传导的靶基因。 转录组分析以及染色质占用和结构分析此外，我将使用单细胞。 正常和 DBA 患者骨髓造血祖细胞的 RNA 测序进行比较 糖皮质激素和 TGFβ 对小鼠红细胞生成和人类红细胞生成的影响。 (i) 广泛地促进我们对骨髓衰竭的病理生理学和治疗原则的理解， (ii) 进一步发展我早期博士后工作中产生的发育生物学新领域，以及 (iii) 为我向独立过渡提供充足的机械和转化后续行动机会。 我是一名医师科学家，正在寻求 K08 支持，以在 Harvey Lodish 博士的指导下开展指导性研究 Stuart Orkin 博士在这段指导期间将投入 80% 的研究和职业发展时间以及 20% 的临床时间。 确保我获得成为一名成功的独立首席研究员所需的技能。 Orkin 是国际公认的导师，共同培训了超过 200 名成功的独立调查员； 我获得了美国血液学会基础科学导师奖，我的培训将在两个世界- 类机构、怀特海德生物医学研究所和丹娜法伯/波士顿儿童医院 癌症和血液疾病中心都为年轻科学家提供了丰富的培训和高度追求的机会。 我还将受到一个研究人员委员会的指导。 都是各自领域的领导者：David Bartel 博士（RNA 生物学）、Peter Reddien（发育生物学）和 Akiko 博士 Shimamura（骨髓衰竭）。K08 奖项的支持将使我能够专注于成熟我的研究。 并在指导培训的最后阶段加强我的职业发展。 在我的获奖期间，我将处于最佳位置，作为一名独立的医师科学家取得成功。