Role of Angiogenin in Hematopoietic Stem Cell Quiescence and Self-renewal

血管生成素在造血干细胞静止和自我更新中的作用

• 批准号: 8909780
• 负责人: Kevin A Goncalves
• 金额: $ 3.89万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909780
• 关键词: ANG gene; Address; Apoptotic; Binding; Biogenesis; Biological Assay; Blood; Blood Cells; Bone Marrow; Bone Marrow Diseases; Bone Marrow Transplantation; Bromodeoxyuridine; Cancer Model; Cell Cycle; Cell Line; Cell Proliferation; Cell Surface Receptors; Cells; Chronic Myeloid Leukemia; Clinical; Clinical Research; Defect; Development; Developmental Process; Disease; Effectiveness; Equilibrium; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Homing; Human; In Vitro; Knock-out; Knockout Mice; Lead; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Modeling; Mus; Myeloproliferative disease; Nuclear Translocation; Pathway interactions; Patients; Physiological; Prevention; Production; Property; Protein Biosynthesis; Proteins; Proteomics; Recombinant Proteins; Regenerative Medicine; Regulation; Ribonucleases; Ribosomal RNA; Role; Source; Stem cell transplant; Stem cells; Therapeutic; Transplantation; Up-Regulation; aged; angiogenin; base; bcr-abl Fusion Proteins; cancer cell; cell behavior; cell growth; exhaustion; in vitro activity; in vivo; in vivo Model; leukemic stem cell; leukemogenesis; malignant state; mouse model; neutralizing antibody; new therapeutic target; novel; plexin; primitive cell; programs; public health relevance; receptor; self-renewal; stem cell biology; stem cell niche; stem cell population; therapeutic target; transplantation medicine; tumorigenesis

 DESCRIPTION (provided by applicant): Angiogenin (ANG) is an angiogenic ribonuclease that has been shown by our lab to promote cancer cell proliferation by stimulating growth and survival pathways. We recently identified ANG as a novel regulator of hematopoietic stem cell (HSC) quiescence, suggesting that ANG differentially regulates cell growth in primitive versus mature cells. Quiescence is a vital property of stem cells, and is critical to maintaining normal stem cell behavior during crucial normal developmental processes, including hematopoiesis. Despite its protective role against stem cell exhaustion and malignancy, little is known about the factors that regulate HSC quiescence. We have demonstrated significantly elevated expression of ANG in primitive HSC populations and shown ANG control of stem cell pool size, cell cycle status, apoptotic activity, blood lineage differentiation, colony number, and mobilization. We also demonstrated stem cell exhaustion in a serial bone marrow (BM) transplantation model, indicating loss of quiescence in the absence of ANG. Moreover, several clinical studies have identified ANG as a factor upregulated in various hematological malignancies, including chronic myelogenous leukemia (CML), and aged Ang-/- mice develop a myeloproliferative disorder. This proposal aims to understand the exact functional role and mechanistic action of ANG during normal and malignant hematopoiesis. Based on our initial studies, we hypothesize that ANG controls stem cell quiescence in both a cell-autonomous and a non-cell autonomous manner during normal hematopoiesis, and the homeostatic control of ANG is disrupted in the malignant state. In this study we will (1) establish the requirement of ANG for HSC activity in vitro and in vivo, (2) determine the mechanism by which ANG maintains HSC quiescence, and (3) investigate the role of ANG and its receptor in leukemogenesis. Given that ANG has been shown to regulate quiescence, at least in part, in a non-cell autonomous manner in BM, we propose to identify the physiologically-relevant cell-of-origin of ANG in the BM niche using conditional knockout models developed by our lab. We will also identify the receptor through which ANG promotes HSC quiescence non-cell autonomously, and demonstrate therapeutic potential of this axis in vitro and in vivo. Moreover, we will identify ANG as a novel regulator of ribosomal activity and protein synthesis in HSCs and leukemia, and identify novel downstream targets in regulating quiescence. Last, we will examine its function and mechanism using a BCR-ABL model of leukemogenesis. Our study will identify ANG as a novel factor that is simultaneously a conductor of the quiescent state in normal HSCs and a potent regulator of the leukemic state. Since the homeostatic balance of critical stem cell properties is necessary for maintained blood production and prevention of malignant transformation, the understanding of factors that uniquely regulate this balance, such as ANG, is necessary for the development of key therapeutics in a variety of BM disorders, hematological malignancies, and in regenerative medicine.

 描述（由适用提供）：血管生成蛋白（ANG）是一种血管生成核糖核酸酶，我们的实验室已显示，通过刺激生长和生存途径来促进癌细胞的增殖。我们最近将ANG确定为造血干细胞（HSC）静止的新型调节剂，这表明ANG对原始细胞和成熟细胞的细胞生长有所不同。静止是干细胞的重要特性，对于在包括造血的关键正常发育过程中维持正常的干细胞行为至关重要。尽管具有防止干细胞衰竭和恶性肿瘤的保护作用，但对调节HSC静止的因素知之甚少。我们已经证明，在原始HSC种群中，ANG的表达显着升高，并显示了干细胞池大小，细胞周期状态，凋亡活性，血统分化，菌落数和动员的控制。我们也是 在连续骨髓（BM）移植模型中证明了干细胞的衰竭，表明在没有ANG的情况下静止。此外，一些临床研究已将ANG确定为各种血液系统恶性肿瘤的一个因素，包括慢性骨髓性白血病（CML）和老化的ANG - / - 小鼠患有骨髓增生障碍。该建议旨在了解正常和恶性造血作用在正常和恶性造血中的确切功能作用和机械作用。基于我们的初步研究，我们假设ANG在正常造血症中控制了细胞自主和非细胞自主性方式的干细胞静止，并且在恶性状态下，ANG的体内平衡控制受到了破坏。在这项研究中，（1）在体外和体内确定ANG对HSC活性的要求，（2）确定ANG保持HSC静止的机制，以及（3）研究ANG及其受体在白血病发生中的作用。鉴于ANG已被证明至少部分地以BM中的非细胞自主方式调节静态，我们建议使用我们实验室开发的条件敲除模型来鉴定BM壁niche中ANG的物理相关的Origin。我们还将确定ANG促进HSC静止的受体，并在体外和体内证明该轴的治疗潜力。此外，我们将确定ANG是一个新颖的调节器 HSC和白血病中的核糖体活性和蛋白质合成，并确定调节静止中的新型下游靶标。最后，我们将使用白血病的BCR-ABL模型检查其功能和机制。我们的研究将ANG识别为新的因素，它只是正常HSC中静态状态的指挥和白血病的潜在调节剂。由于关键干细胞特性的稳态平衡对于维持血液产生和预防恶性转化是必要的，因此对唯一调节这种平衡的因素（例如ANG）的理解对于在多种BM疾病，血液学恶性肿瘤和再生药物中开发关键疗法是必要的。