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: 10280176
• 负责人: Adolfo A. Ferrando
• 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/10280176
• 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.

项目总结/文摘