Ing4-deficiency enhances the regenerative capacity of multipotent progenitor cells

Ing4缺陷增强多能祖细胞的再生能力

• 批准号: 10452422
• 负责人: Katie L Kathrein
• 金额: $ 10.63万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452422
• 关键词: Acetylation; Address; Animals; Apoptosis; Binding; Biogenesis; Biological Assay; Blood Cells; Bone Marrow; Cell Cycle; Cell Lineage; Cell Ontogeny; Cell physiology; Cells; Characteristics; Chimerism; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Data; Development; Disease; Engraftment; Epigenetic Process; Foundations; Future; Gene Expression; Genes; Genetic Screening; Goals; Grant; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histone Acetylation; Histones; In Vitro; Individual; Inflammatory; Lead; Marrow; Modeling; Molecular; Molecular Profiling; Multipotent Stem Cells; Mus; NF-kappa B; Non-Malignant; Output; PHD Finger; Pathway interactions; Patients; Phenotype; Plants; Population; Process; Proliferating; Property; Proteins; Regenerative capacity; Repression; Research; Ribosomes; Role; Sickle Cell Anemia; Signal Transduction; Stem cell transplant; Suppressor Genes; TP53 gene; Testing; Thalassemia; Transplant Recipients; Transplantation; Work; base; bone marrow failure syndrome; c-myc Genes; hematopoietic stem cell differentiation; hematopoietic stem cell fate; improved; in vivo; indexing; inhibitor; member; post-transplant; reconstitution; reverse genetics; self renewing cell; self-renewal; small molecule; stem cell biology; stem cell differentiation; stem cell function; stem cell population; stem cell self renewal; stem cells; stem-like cell; success; therapeutic target

Project summary/Abstract. Long-term hematopoietic stem cells (HSCs) are capable of self-renewal and differentiation into all mature hematopoietic lineages. The established paradigm for this process involves the self-renewal and differentiation of HSCs into progenitor cells. The primary goal of our proposal is to define mechanisms to enhance self-renewal in stem and progenitor cells for hematopoietic stem cell transplantation in patients. A steady rise in patients receiving HSC transplants for non-malignant diseases and disorders has occurred over the last two decades, but survival of these patients can be as low as 20-40% in the five year post-transplant period. This suggests a strong need for improved HSC transplants for these patients. To advance our understanding of HSC function and self-renewal, I completed the first large-scale in vivo reverse genetic screen targeting chromatin factors, which regulate gene expression through changes in chromatin structure. From this screen, we found a requirement for the plant homeodoming (PHD) finger and chromatin associated protein, Ing4. As a member of the Hbo1 chromatin remodeling complex, Ing4 binds to target loci through recognition of H3K4me3 marks and increases localized levels of histone acetylation. Ing4 has also been shown to negatively regulate NF-κB, c-Myc, Hif1a, and p53. Our work in Ing4-deficient mice has shown that loss of Ing4 has a dramatic effect on hematopoiesis in the bone marrow. These mice show increased levels of HSCs and a loss of multipotent progenitors (MPPs). Transplantation of MPPs shows that while there are fewer MPPs, the cells that do differentiate to the MPP stage are more capable of robust, long-term reconstitution than their wild-type counterparts, showing very high levels of chimerism up to 9 months post- transplant. We hypothesize that Ing4 regulates self-renewal properties in MPP cells and loss of Ing4 results in MPPs with activated stem cell-like properties. Work done under this proposal will identify the pathways altered in Ing4-deficient MPPs to characterize how they have regained the ability to function like HSCs. If successful, our studies will provide a new mechanism for re-activating self-renewal pathways. This could lead to more successful HSC transplants for patients needing this treatment.

项目摘要/摘要。长期造血干细胞（HSC）能够自我更新和 分化为所有成熟的造血谱系。该过程的既定范式涉及 HSC自我更新和分化为祖细胞。我们建议的主要目标是定义 增强造血细胞移植的茎和祖细胞中自我更新的机制 患者。接受非恶性疾病和疾病的HSC移植的患者的稳定增加已有 发生在过去的二十年中，但是这些患者的存活率可能低至20-40％ 移植后期。这表明对这些患者的HSC移植物有很强的需求。到 促进我们对HSC功能和自我更新的理解，我完成了第一个大规模的体内大规模反向 遗传筛选靶向染色质因子，该因子通过染色质变化来调节基因表达 结构。在此屏幕上，我们发现了植物同源（PHD）手指和染色质的要求 相关蛋白质，ING4。作为HBO1染色质重塑复合物的成员，ING4与靶基因座结合 通过识别H3K4me3标记并增加了组蛋白乙酰化的局部水平。 ING4也有 我们被证明对NF-κB，C-MYC，HIF1A和p53进行负调节。我们在ING4缺陷小鼠中的工作已显示 ING4的损失对骨髓中的造血作用产生巨大影响。这些老鼠显示出增加 HSC的水平和多能祖细胞（MPP）的损失。 MPPS的移植表明在那里 较少的MPP，与MPP阶段不同的细胞更能坚固，长期 重构比其野生型对应物，在9个月后长达9个月的嵌合体表现出很高 移植。我们假设ING4调节MPP细胞中的自我更新特性和ING4的丧失 导致具有活化干细胞样性能的MPP。根据本提案完成的工作将确定 ING4缺陷MPP中改变的途径以表征它们如何继续运作的能力 像HSC。如果成功，我们的研究将为重新激活自我更新途径提供新的机制。 这可能会导致需要此治疗的患者更成功的HSC移植。