Regulation of normal and leukemic hematopoiesis by type I interferon

I 型干扰素对正常和白血病造血的调节

• 批准号: 8127112
• 负责人: Eric M Pietras
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127112
• 关键词: Address; Affect; Antiviral Agents; Apoptosis; Autoimmune Diseases; Biology; Blood Cells; Bone Marrow Cells; Cells; Cellular biology; Chronic; Chronic Myeloid Leukemia; Clinic; Clinical; Cues; Data; Development; Equilibrium; Exposure to; Family; Goals; Health; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Human; Imatinib; In Vitro; Infection; Inflammatory; Interferon Type I; Interferons; Knowledge; Lead; Leukemic Hematopoietic Stem Cell; Mediating; Modality; Molecular; Myelogenous; Myeloid Progenitor Cells; Myeloproliferative disease; Play; Poly I-C; Population; Population Decreases; Predisposition; Process; Proliferating; Property; Proteins; Public Health; Regulation; Roche brand of peginterferon alfa-2a; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Stem cells; Stress; Therapeutic Intervention; Toxic effect; Transgenic Mice; Tyrosine Kinase Inhibitor; Wild Type Mouse; Work; base; bcr-abl Fusion Proteins; cell type; chemotherapeutic agent; combinatorial; cytokine; design; hematopoietic stem cell fate; in vivo; interest; kinase inhibitor; mouse model; novel; progenitor; response; self renewing cell; self-renewal; stem

DESCRIPTION (provided by applicant): The goals of this project are to define the mechanisms by which type I IFNs alter the fates of immature hematopoietic stem cells (HSCs) and progenitor cells, and to identify the effect and underlying mechanisms of type I IFNs on the health and potential of normal and leukemic HSCs. These studies will be carried out using HSCs and progenitor cells isolated from wild-type mice and from the SCLtTAxBCR/ABL double transgenic mouse model of human chronic myelogenous leukemia (CML), and a comprehensive array of in vivo and in vitro experimental approaches. In the first aim, we will investigate how short-term (days) and long-term (weeks) exposure to type I IFNs affects the biology of HSCs and progenitor cells with respect to their quiescence, proliferation, potential, and susceptibility to apoptosis. We will also examine whether chronic (months) exposure to type I IFNs damages HSC self-renewal. Lastly, we will define the molecular mechanisms underlying these changes. In the second aim, we will assess how type I IFNs affect the biology of leukemic HSCs and progenitor cells compared to wild type cells. We will investigate how the deregulated properties of BCR/ABL-expressing leukemic HSCs (i.e., increased proliferation, decreased quiescence, increase survival) change their response to type I IFNs exposure and may sensitize them to combinatorial treatments with type I IFNs and the BCR/ABL tyrosine kinase inhibitor, Imatinib. Taken together, these approaches should uncover how inflammatory signals such as type I IFNs impact on the regulatory networks that normally control HSC and progenitor cell homeostasis, and how the deregulated properties of leukemic HSCs may alter their sensitivity to the effects of inflammatory signals and therapeutic interventions. PUBLIC HEALTH RELEVANCE: This project seeks to understand how type I interferons (IFNs), a large family of inflammatory proteins, affects the biology of hematopoietic stem cells (HSCs), a small population of bone marrow cells that generate all blood cells. Improper regulation of HSC activity can lead to a number of severe blood diseases. These include chronic myelogenous leukemia (CML), which has long been treated with type I IFNs despite the lack of knowledge regarding their mechanism of action. Recent clinical work suggests that type I IFNs may enhance the curative effect of other CML treatments, such as the tyrosine kinase inhibitor Imatinib. By uncovering how type I IFNs affect the biology of normal and leukemic HSCs, and the molecular mechanisms underlying these effects, the proposed work could be of significant value to public health by providing the basis for the design of more effective co-treatments for CML and other blood diseases that will harness the beneficial effect of type I IFNs.

描述（由申请人提供）：本项目的目标是确定I型IFN改变未成熟造血干细胞（HSC）和祖细胞命运的机制，并确定I型IFN对正常和白血病HSC的健康和潜能的影响和潜在机制。这些研究将使用从野生型小鼠和人慢性髓性白血病（CML）的SCLtTAxBCR/ABL双转基因小鼠模型中分离的HSC和祖细胞，以及一系列全面的体内和体外实验方法进行。在第一个目标中，我们将研究短期（数天）和长期（数周）暴露于I型IFN如何影响HSC和祖细胞的生物学特性，包括它们的静止、增殖、潜力和对凋亡的敏感性。我们还将研究慢性（数月）暴露于I型干扰素是否会损害HSC的自我更新。最后，我们将定义这些变化背后的分子机制。在第二个目标中，我们将评估与野生型细胞相比，I型IFN如何影响白血病HSC和祖细胞的生物学。我们将研究表达BCR/ABL的白血病HSC的失调特性（即，增加的增殖、减少的静止、增加的存活）改变了它们对I型IFN暴露的应答，并且可以使它们对I型IFN和BCR/ABL酪氨酸激酶抑制剂伊马替尼的组合治疗敏感。总之，这些方法应该揭示炎症信号，如I型IFN如何影响通常控制HSC和祖细胞稳态的调节网络，以及白血病HSC的失调特性如何改变其对炎症信号和治疗干预的敏感性。 公共卫生相关性：该项目旨在了解I型干扰素（IFN），一个大家族的炎症蛋白，如何影响造血干细胞（HSC）的生物学，造血干细胞是一小群骨髓细胞，产生所有血细胞。对HSC活性的不当调节可导致许多严重的血液疾病。这些包括慢性粒细胞白血病（CML），长期以来一直用I型IFN治疗，尽管缺乏关于其作用机制的知识。最近的临床研究表明，I型干扰素可能会增强其他CML治疗的疗效，如酪氨酸激酶抑制剂伊马替尼。通过揭示I型干扰素如何影响正常和白血病HSC的生物学，以及这些影响的分子机制，拟议的工作可能对公共卫生具有重要价值，为设计更有效的CML和其他血液疾病的联合治疗提供基础，这些疾病将利用I型干扰素的有益作用。