Scribble in hematopoietic stem cell activity

造血干细胞活性的涂鸦

• 批准号: 9934991
• 负责人: Mark Jordan Althoff
• 金额: $ 3.75万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934991
• 关键词: Asses; Blood Cells; Bone Marrow; Cell Cycle; Cell Cycle Inhibition; Cell Cycle Progression; Cell Differentiation process; Cell Polarity; Cell Proliferation; Cell physiology; Cells; Chronic Disease; Complex; Confocal Microscopy; Cues; Cytoplasm; Data; Development; Disease; Euchromatin; Exhibits; Failure; Flow Cytometry; Genetic; Genetic Diseases; Genetic Transcription; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; 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; Pharmacology; 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; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; improved; in vivo; insight; leukemia; member; mutant; novel; polarized cell; 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.