Scribble in hematopoietic stem cell activity

造血干细胞活性的涂鸦

• 批准号: 9122838
• 负责人: Mark Jordan Althoff
• 金额: $ 3.6万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122838
• 关键词: Asses; Blood Cells; Bone Marrow; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cell Polarity; Cell Proliferation; Cell physiology; Cells; Chronic Disease; Complex; Confocal Microscopy; Cues; Cytoplasm; Data; Development; Disease; Euchromatin; Exhibits; Failure; Flow Cytometry; Genetic; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hereditary Disease; Image; Individual; Interferon Type I; Interferons; Intervention; Label; Larva; Leucine-Rich Repeat; Malignant Neoplasms; Measures; Mediating; Mesenchymal Stem Cells; Molecular; Molecular Target; Mus; Nuclear; Nuclear Translocation; Organ Size; Pathway interactions; Phosphorylation; Phosphotransferases; Population; Proteins; Regulation; Research Personnel; Resistance; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Role; STAT1 gene; STAT2 gene; Signal Pathway; Signal Transduction; Stem cell transplant; Stem cells; Stress; Structure; Testing; Therapeutic; Translating; Transplantation; Virus Diseases; Work; cancer genetics; cell behavior; cell type; chemotherapy; cytokine; cytopenia; exhaustion; hematopoietic stem cell fate; improved; in vivo; insight; leukemia; member; mutant; novel; progenitor; programs; public health relevance; reconstitution; response; self-renewal; transcriptome

 DESCRIPTION (provided by applicant): The potential of hematopoietic stem cells (HSC) to reconstitute the hematopoietic system has allowed for the development of transplantation approaches to treat cancer and hematologic diseases. Cell cycle status of HSC defines their ability to engraft in conditioned recipients and has been hypothesized as a mechanism for chemotherapy-resistant HSC-derived leukemias. HSC are highly quiescent cells with the ability to rapidly enter the cell cycle and differentiate through changes in their polarity and disposition of intracellular molecular fate determinants in response to microenvironment (ME) cues. In bone marrow (BM) hematopoiesis, interferons type I (IFN-I), a ME cytokine produced in response to viral infection, have been shown to be a crucial positive regulator to induce proliferation of otherwise quiescent hematopoietic stem cells (qHSC). Our preliminary data indicate that Scribble deficient HSC are insensitive to IFN-I and retain cellular quiescence in vivo. Our preliminary data also show that the Hippo effector Yap1, which also regulates stem cell proliferation in response to ME signals, is polarized and co-localizes in the cytoplasm with Scribble in wild type HSC. Deficiency of Scribble in HSC results in Yap1 translocation to nuclear euchromatin suggesting a novel Scribble-mediated mechanism used to protect qHSC from potential damage associated with cellular activation. Our data suggests that Scribble distinctly regulates HSC cell cycle progression in a context-dependent manner. We believe that ME IFN-I induced HSC proliferative signaling program depends on Scribble and that Scribble deficiency abrogates HSC polarization leading to reduced quiescence and subsequent HSC exhaustion through activation of downstream Hippo effectors. To gain insight into these ME dependent signaling pathways that control HSC activity, we plan to analyze both IFN-I response signaling pathways and Hippo signaling in Scribble proficient and deficient HSC. We will utilize flow cytometry and confocal microscopy to define a role for Scribble in mediating such signals. Functionally, we will test the reconstitution abilities of wild type and Scribble structure-functio mutants in Scribble deficient HSC through serial transplantations. Dissecting the microenvironment dependent Scribble-mediated molecular mechanisms that govern HSC quiescence will help refine the significance and therapeutic potential of naturally occurring IFN molecules and identify novel targets for intervention in HSC disease.

 描述（由适用提供）：造血干细胞（HSC）重建造血系统的潜力允许开发移植方法治疗癌症和血液学疾病。 HSC的细胞周期状态定义了他们在条件受体中植入的能力，并被认为是耐化学疗法的HSC衍生白血病的机制。 HSC是高度静止的细胞，能够快速进入细胞周期并通过其极性和处置来区分 细胞内分子脂肪的响应对微环境（ME）提示决定。在骨髓（BM）造血，I型干扰素（IFN-I）中，一种响应病毒感染产生的ME细胞因子，已被证明是至关重要的阳性调节剂，可诱导原本静态的造血干细胞（QHSC）的增殖。我们的初步数据表明，涂鸦缺乏HSC对IFN-I不敏感并在体内保留细胞静止。初步数据还表明，河马效应子YAP1还根据我的信号调节干细胞增殖，在野生型HSC中与涂鸦在细胞质中具有极化，并在细胞质中共定位。 HSC中涂鸦的缺乏会导致YAP1转移到核塑性素上，这表明一种新型的涂鸦介导的机制，用于保护QHSC免受与细胞激活相关的潜在损害。我们的数据表明，涂鸦以上下文依赖性方式明显地调节了HSC细胞周期的进程。我们认为，我IFN-I诱导HSC增殖信号传导程序取决于涂鸦，并且涂鸦缺乏症A杂志HSC极化导致静脉降低，随后通过激活下游河马效应而导致HSC耗尽。为了深入了解控制HSC活性的这些依赖性信号通路，我们计划分析涂鸦熟练且缺乏不足的HSC中IFN-I响应信号通路和河马信号传导。我们将利用流式细胞仪和共聚焦显微镜来定义涂鸦在介导此类信号中的作用。在功能上，我们将通过连续移植中涂鸦缺陷HSC中野生型和涂鸦结构 - 功能突变体的重建能力。解剖依赖于涂料的微环境介导的分子机制，这些分子机制来控制HSC静止，将有助于提高天然发生的IFN分子的显着性和治疗潜力，并确定对HSC疾病干预的新靶标。