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）：该项目的目标是确定 I 型干扰素改变未成熟造血干细胞（HSC）和祖细胞命运的机制，并确定 I 型干扰素对造血干细胞（HSC）和祖细胞命运的影响和潜在机制。正常和白血病 HSC 的健康状况和潜力。这些研究将使用从野生型小鼠和人类慢性粒细胞白血病 (CML) 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来进行。第一个目标是，我们将研究短期（数天）和长期（数周）暴露于 I 型干扰素如何影响 HSC 和祖细胞的生物学特性，包括静止、增殖、潜力和细胞凋亡的敏感性。我们还将检查长期（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（即增殖增加、静止减少、存活增加）如何改变它们对 I 型 IFN 暴露的反应，并可能使它们对 I 型 IFN 和 BCR/BCR 的组合治疗敏感。 ABL酪氨酸激酶抑制剂，伊马替尼。总而言之，这些方法应该揭示 I 型 IFN 等炎症信号如何影响正常控制 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。 公共健康相关性：该项目旨在了解 I 型干扰素 (IFN)（一大类炎症蛋白）如何影响造血干细胞 (HSC)（生成所有血细胞的一小群骨髓细胞）的生物学特性。 HSC 活性调节不当会导致许多严重的血液疾病。其中包括慢性粒细胞白血病 (CML)，尽管对其作用机制缺乏了解，但长期以来一直采用 I 型干扰素治疗。最近的临床工作表明，I 型干扰素可能会增强其他 CML 治疗的疗效，例如酪氨酸激酶抑制剂伊马替尼。通过揭示 I 型 IFN 如何影响正常和白血病 HSC 的生物学，以及这些影响背后的分子机制，拟议的工作可能对公共健康具有重要价值，为设计更有效的 CML 和白血病联合治疗奠定基础。其他血液疾病将利用 I 型干扰素的有益作用。