The role of PHF6 in the control of hematopoietic stem cell aging.

PHF6在控制造血干细胞衰老中的作用。

• 批准号: 10474570
• 负责人: Teresa Palomero
• 金额: $ 50万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474570
• 关键词: Age; Aging; Anabolism; Animal Model; Biological Assay; Bone Marrow; Cell Adhesion; Cell Aging; Cell Compartmentation; Cell Cycle; Cell Cycle Kinetics; Cell Nucleolus; Cell Proliferation; Cell division; Cell model; Cell physiology; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Colony-Forming Units Assay; Complex; Computational Biology; DNA Damage; Deacetylase; Deterioration; Development; Engraftment; Epigenetic Process; Event; Generations; Genes; Genetic; Genetic Transcription; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homing; Human; Impairment; In Vitro; Inflammation; Inflammatory; Knock-out; Knockout Mice; Life Expectancy; Lymphoid; Mediating; Mediator of activation protein; Metabolism; Molecular; Myelogenous; Nucleosomes; Organ; Pathology; Phenotype; Plants; Play; Population; Population Decreases; Positioning Attribute; Proteins; Regulation; Ribosomes; Role; Somatic Mutation; Testing; Therapeutic Intervention; Translations; Transplantation; aged; analytical tool; cell age; cell motility; conditional knockout; cytokine; epigenomics; exhaust; experimental study; fitness; functional decline; genome integrity; hematopoietic stem cell aging; hematopoietic stem cell self-renewal; homeodomain; improved; in vivo; leukemic transformation; new therapeutic target; programs; replication stress; response; self-renewal; senescence; stem; stem cell aging; stem cell function; stem cells; therapeutic development; transcriptomics

Project Summary/Abstract As life expectancy increases age-associated pathologies have become a major health problem. It is now recognized that stem cell aging is a driver of systemic and organ-specific functional decline. In the hematopoietic system stem cell aging is characterized by accumulation of immunophenotypically-defined hematopoietic stem cells (HSCs) with impaired self-renewal capacity and altered differentiation programs with increased generation of myeloid populations and decreased lymphoid potential. Here we show that genetic loss of Plant Homeodomain Factor 6 (PHF6) results in increased HSC serial transplantation capacity and abrogates the development of age-associated hematopoietic decay including the accumulation of functionally exhausted HSCs displaying myeloid differentiation bias and impaired lymphoid potential. Our central hypothesis is that loss of Phf6 reconfigures the epigenetic landscape of HSCs blocking the initiation and/or progression of age-associated functional decline. Here we will apply the combined expertise of the Ferrando and Rabadan labs in hematopoiesis and computational biology to explore in depth the hematopoietic phenotypes and mechanisms of PHF6 inactivation in HSC aging. Towards this goal we will analyze the stem cell compartment in Phf6 conditional knockout mice and after CRISPR-directed PHF6 inactivation in human hematopoietic stem cells, leveraging in vitro and in vivo stem cell assays in combination with advanced computational analytical tools applied to single cell transcriptomics and epigenomics. These studies will ultimately facilitate the development of new targeted therapies aimed at improving the engraftment capacity of hematopoietic stem cells from aged donors and for the treatment of pathologies resulting from age-associated HSC deterioration.

项目摘要/摘要 随着预期寿命的增加，与年龄相关的疾病已经成为一个主要的健康问题。 现在已经认识到，干细胞老化是全身和器官特异性功能的驱动因素 拒绝。在造血系统中，干细胞老化的特征是 免疫表型定义的造血干细胞(HSCs)自我更新受损 随着髓系群体世代的增加，能力和分化程序的改变 并降低了淋巴潜能。在这里，我们展示了植物同源域的遗传损失 因子6(PHF6)导致HSC系列移植能力增加，并废除 年龄相关的造血衰退的发展，包括功能上的积累 衰竭的HSCs表现为髓系分化偏向和淋巴潜能受损。我们的 中心假说是Phf6的丢失重新配置了HSCs阻断的表观遗传格局 与年龄相关的功能衰退的开始和/或进展。在这里，我们将应用 费兰多和拉巴丹实验室在造血和计算方面的综合专业知识 生物学深入探讨PHF6失活的造血表型和机制 在HSC老化过程中。为了达到这个目标，我们将分析Phf6条件下的干细胞室。 基因敲除小鼠和CRISPR诱导的人造血干细胞PHF6失活 利用体外和体内干细胞分析与先进的 应用于单细胞转录和表观基因组学的计算分析工具。这些 研究最终将促进新的靶向疗法的发展，旨在改善 老年供者造血干细胞植入能力的研究及临床应用 由年龄相关的HSC恶化引起的病理。