Lineage Determination and Tissue HomeOstasis in the aged Hematopoietic System

描述(申请人提供)：造血涉及紧密协调的血细胞生产过程，由少量的造血干细胞(HSCs)维持。与年轻人相比，老年人在包括造血系统在内的各种组织和器官的基线功能和适应能力显著下降。据推测，随着年龄的增长，这些造血功能的变化是导致老年人贫血和免疫功能下降的根本原因之一，尤其是在压力下。确定积极促进造血的造血干细胞及其后代的数量并追踪单个造血干细胞对不同血细胞系的贡献是确定组织内稳态效率降低的细胞基础的重要一步。这项研究的主要目标是在克隆水平上确定衰老后造血效率降低的细胞和分子基础，长期目标是将这一知识转化为治疗方法，以改善甚至逆转造血系统中不需要的年龄相关表型。我们将使用通过短期(4小时)转导(体外)自失活慢病毒载体对单个小鼠HSCs进行克隆条码编码的新技术来单独标记大量HSCs，以确定造血系统中的克隆性、谱系确定和细胞周转以及这些参数随年龄的变化。

DESCRIPTION (provided by applicant): Hematopoiesis involves the tightly coordinated process of blood cell production and is maintained by a small number of hematopoietic stem cells (HSCs). Compared to the young, the elderly show a substantial decline of baseline functions and adaptive capacity in various tissues and organs, including the hematopoietic system. It is assumed that these changes in hematopoiesis with age comprise one of the underlying causes for anemia and reduced immune function in the elderly, especially under stress. Resolving the number of HSCs and their progeny that actively contribute to hematopoiesis and tracking the contribution of individual HSCs to each of the different blood cell lineages is an important step to determine the cellular basis for decreased efficiency in tissue homeostasis. The primary goal of this study is to determine, on a clonal level, the cellular and molecular basis for decreased efficiency in hematopoiesis upon aging, with the long-term goal to translate this knowledge into therapies to ameliorate or even revert unwanted age-associated phenotypes in the hematopoietic system. We will use the novel technology of clonal barcoding of individual murine HSCs by short-term (4 hours) transduction (ex vivo) with self-inactivating lentiviral vectors to individually mark a multitude of HSCs to determine clonality, lineage determination and cell turnover in the hematopoietic system and the changes in these parameters associated with aging.