Lineage Determination and Tissue HomeOstasis in the aged Hematopoietic System

老年造血系统的谱系测定和组织稳态

基本信息

批准号：
8306700
负责人：
HARTMUT GEIGER
金额：
$ 34.43万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306700
关键词：
Affect Age Aging Anemia Animals Blood Blood Cells Bone Marrow Cell Aging Cell Lineage Cells Clonality Collection Data Elderly Environment Erythropoiesis Family Future Genes Goals Guanosine Triphosphate Phosphohydrolases Harvest Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Hour Human Inbreeding Individual Knowledge Lentivirus Vector Longevity Lymphoid Maintenance Molecular Mononuclear Morbidity - disease rate Mus Myeloid Cells Organ Phenotype Play Premature aging syndrome Process Production Publishing Reporting Role Signal Transduction Stem cells Stimulus Stress Systems Analysis Testing Tissues Transducers Translating Transplantation Viral age effect aged base cell age cell determination genome wide association study immune function in vivo inhibitor/antagonist juvenile animal lentivirally transduced new technology novel repaired rho self-renewal stem cell differentiation tool

项目摘要

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.

描述（由申请人提供）：造血涉及血细胞生成的紧密协调过程，并由少量造血干细胞（HSC）维持。与年轻人相比，老年人包括造血系统在内的各组织器官的基线功能和适应能力均明显下降。据认为，造血随年龄的变化是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。确定对造血作出积极贡献的 HSC 及其后代的数量，并追踪单个 HSC 对每种不同血细胞谱系的贡献，是确定组织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时造血效率降低的细胞和分子基础，长期目标是将这些知识转化为治疗方法，以改善甚至恢复与年龄相关的不良表型在造血系统中。我们将使用自我失活慢病毒载体通过短期（4小时）转导（离体）对单个小鼠 HSC 进行克隆条形码的新技术，单独标记大量 HSC，以确定细胞中的克隆性、谱系确定和细胞更新。造血系统以及这些参数的变化与衰老相关。