Aging, hematopoietic stem cells, gene expression and clonality, cell by cell

衰老、造血干细胞、基因表达和克隆性，逐个细胞

• 批准号: 497790916
• 负责人: Professor Dr. Hartmut Geiger
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497790916?language=en
• 关键词: Aging; hematopoietic; stem; cells; gene

Aging is thought to contribute to aging-associated leukemia like myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Age-related clonal hematopoiesis (ARCH or simply CH) is defined as the gradual, clonal expansion of hematopoietic stem and progenitor cells (HSPCs) carrying specific, disruptive, and recurrent genetic variants without clear diagnosis of hematological malignancies. CH is regarded to be the initiating step for MDS and/or AML. Understanding how CH develops and why it is linked to aging is a prerequisite to design rationale approaches to target CH and thus to reduce the initiation of aging-associated MDS or AML. We propose to perform single cell sequencing (384 cells per individual donor) on HSCs, multi-potent progenitors (MPPs) and hematopoietic progenitor cells (HPCs) from young and older adults with SMART-Seq2 technology to apply novel, innovative analyses to determine true single nucleotide variants (SNVs, aka mutations) and gene expression profiles. Based on this data, we will determine clonality in hematopoiesis (HSCs, MPPs, HPCs and in BM) in individuals and among individuals to ultimately provide a comprehensive view at which step in hematopoiesis clonality develops and which genes are affected. We anticipate that the data and the analyses based on the data will become a highly valued resource for the international scientific community and will move the field significantly forward.

衰老被认为会导致与衰老相关的白血病，如骨髓增生异常综合征（MDS）或急性髓性白血病（AML）。年龄相关性克隆造血（ARCH或简称CH）被定义为携带特异性、破坏性和复发性遗传变异的造血干细胞和祖细胞（HSPCs）的逐渐克隆扩增，没有明确的血液系统恶性肿瘤诊断。CH被认为是MDS和/或AML的起始步骤。了解CH如何发展及其与衰老相关的原因是设计针对CH的基本方法的先决条件，从而减少与衰老相关的MDS或AML的启动。我们建议使用SMART-Seq2技术对来自年轻人和老年人的造血干细胞、多能祖细胞（MPPs）和造血祖细胞（HPCs）进行单细胞测序（每个供体384个细胞），以应用新颖、创新的分析来确定真正的单核苷酸变异（snv，又称突变）和基因表达谱。基于这些数据，我们将确定个体和个体之间造血（hsc、mpp、HPCs和BM）的克隆性，以最终提供一个全面的观点，即造血克隆在哪一步发展，哪些基因受到影响。我们预计，这些数据和基于这些数据的分析将成为国际科学界高度重视的资源，并将大大推动该领域向前发展。