Uncovering the role for Msi2 in hematopoietic stem cells

揭示 Msi2 在造血干细胞中的作用

• 批准号: 9525948
• 负责人: Michael Kharas
• 金额: $ 39.58万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9525948
• 关键词: Address; Adult; Affect; Anemia; Binding; Binding Proteins; Biology; Blood; Bone Marrow; Cell Compartmentation; Cell Count; Cell Cycle; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell division; Cell physiology; Cells; Complex; Defect; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Epigenetic Process; Equilibrium; Etiology; Event; Family; Future; GFI1 gene; Gene Family; Genetic; Germ; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; High-Throughput Nucleotide Sequencing; Immune system; Immunoprecipitation; Knock-out; Lymphoid; MADH3 gene; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Morphology; Mus; Myelogenous; NUP98 gene; Neurons; Normal Cell; Pathogenesis; Pathway interactions; Patient risk; Patients; Phenotype; Post-Transcriptional Regulation; Process; Proteins; RNA; RNA Recognition Motif; RNA Stability; RNA-Binding Proteins; Regulation; Reporter; Role; Signal Transduction; Stem cells; System; TGFBR1 gene; Therapeutic; Therapeutic Intervention; Tissues; Translations; Untranslated Regions; Work; base; bone marrow failure syndrome; crosslink; crosslinking and immunoprecipitation sequencing; cytopenia; gain of function; genetic approach; high risk; insight; loss of function; model development; mouse model; novel; novel strategies; novel therapeutic intervention; overexpression; progenitor; programs; public health relevance; selective expression; self-renewal; small hairpin RNA; stem cell biology; stem cell division; stem cell fate; tool; transcription factor; transcriptome

DESCRIPTION (provided by applicant): Hematopoietic stem cell (HSC) numbers are carefully maintained by switching from symmetric to asymmetric cell divisions. A complex program made of genetic and epigenetic mechanisms that maintain normal HSCs can become dysregulated in hematopoietic disorders and malignancies. Myelodysplastic syndromes (MDS) are characterized as a clonally derived set of heterogeneous diseases demonstrating defective hematopoietic differentiation. Taken together with recent discoveries in the genetic landscape of MDS, the etiology of this disease is considered to be driven by an HSC or an early myeloid progenitor. Thus, dysregulation of cell fate decisions including the balance of asymmetric and symmetric cell division could explain how certain lineages are blocked or why self-renewal is altered. RNA binding proteins in the Msi family have been shown to be important for the switch between symmetric and asymmetric cell division in germ and tissue stem cell function, neural cell differentiation and cell fate determination. Recent studies have implicated MSI2 as a regulator of HSC function and this proposal utilizes Msi2 conditional knockouts and gain of function approaches to dissect the precise role for MSI2 in controlling asymmetric division, self-renewal and cell fate determination. Moreover, this proposal incorporates high throughput sequencing UV-crosslinking immunoprecipitation to identify global RNA targets (HITS-CLIP) that will be used to elucidate the direct mechanism for MSI2 in hematopoietic cells. Furthermore, our global genetic approaches have already uncovered how regulation of translation alters several developmental pathways. MSI2 has also been recently shown to be dysregulated in MDS within "low- risk" patients, expressing below normal levels and within "high-risk" patients demonstrating elevated MSI2 expression. This proposal utilizes the NUP98-HOXD13 MDS murine model combined with novel gain and loss of function MSI2 mouse models to study the initial stages of MDS within the HSC. We suggest that MSI2 dysregulation contributes to the biology of hematopoietic disorders and thus a deeper understanding of these mechanisms will provide additional therapeutic approaches.

描述（由申请人提供）：通过从对称细胞分裂转换为不对称细胞分裂，小心维持造血干细胞（HSC）数量。由维持正常HSC的遗传和表观遗传机制组成的复杂程序在造血系统疾病和恶性肿瘤中可能变得失调。骨髓增生异常综合征（MDS）的特征是一组克隆来源的异质性疾病，表现出造血分化缺陷。结合MDS遗传格局的最新发现，认为该疾病的病因是由HSC或早期髓系祖细胞驱动的。因此，细胞命运决定的失调，包括不对称和对称细胞分裂的平衡，可以解释某些谱系是如何被阻断的，或者为什么自我更新被改变。Msi家族中的RNA结合蛋白已被证明对于生殖和组织干细胞功能、神经细胞分化和细胞命运决定中的对称和不对称细胞分裂之间的转换是重要的。最近的研究已经暗示MSI 2作为HSC功能的调节剂，并且该提议利用MSI 2条件性敲除和功能获得方法来剖析MSI 2在控制不对称分裂、自我更新和细胞命运决定中的精确作用。此外，该提议结合了高通量测序UV交联免疫沉淀以鉴定将用于阐明造血细胞中MSI 2的直接机制的全局RNA靶标（HITS-CLIP）。此外，我们的全球遗传学方法已经揭示了翻译调节如何改变几种发育途径。最近还显示MSI 2在“低风险”患者中的MDS中失调，表达低于正常水平，并且在“高风险”患者中表现出升高的MSI 2表达。该提议利用NUP 98-HOXD 13 MDS鼠模型与新的功能获得和丧失MSI 2小鼠模型组合来研究HSC内MDS的初始阶段。我们认为，MSI 2失调有助于造血系统疾病的生物学，因此对这些机制的更深入了解将提供额外的治疗方法。