Genetic Reg. of Hematopoietic Stem Cell Mobilization

从骨髓到外周血中动员造血干细胞和祖细胞是一种生物学现象，在分子水平上尚不清楚，其生理意义也知之甚少。值得注意的是，人和小鼠在动员造血干细胞和祖细胞(HSPC)的能力上存在显着的个体间差异和品系间差异，这表明存在动员的遗传调节。在小鼠系统中，11号染色体上的一个基因座与粒细胞集落刺激因子(G-CSF)诱导的干细胞动员熟练程度的菌株间变异有关。调控这种变异的一个或多个基因可能在HSPC的定位和运输中发挥重要作用。随着临床对造血干细胞治疗的需求日益增加，了解干细胞定位、动员和运输的生理调节将是非常重要的。这一建议旨在通过产生亚基因动物和随后通过RNA干扰对与动员连锁的基因组区间中的单个基因进行功能分析来鉴定11号染色体上的基因，该基因是HSPC动员的生理调节基因。我们还将分析该基因座/基因在HSPC跨内皮细胞迁移和黏附中的作用。最后，在竞争性移植/动员试验中使用同源动物，我们将分析动员熟练程度与HSPC转运到非造血区(例如肌肉组织)或其他造血区之间的相关性。

Mobilization of hematopoietic stem and progenitor cells (HSPCs) from bone marrow into peripheral blood is a biological phenomenon that is not understood at the molecular level and little is known about the physiologic importance of it. It is notable that there is significant inter-individual variability in humans and inter-strain variability in mice in the ability to mobilize hematopoietic stem and progenitor cells (HSPCs) suggesting that there is genetic regulation of mobilization. In the murine system, a locus on chromosome 11 has been linked to an inter-strain variation in granulocyte colony- stimulating factor (G-CSF) induced stem cell mobilization proficiency. The gene or genes regulating this variation may play an important role in localization and in trafficking of HSPCs. As there is a growing clinical need for hematopoietic stem cell based therapies, it will be important to understand the physiological regulation of stem cell localization, mobilization, and trafficking. This proposal aims at the identification of the gene on chromosome 11 that is a physiologic regulator of HSPC mobilization by generating sub-congenic animals and subsequent functional analysis of individual genes in the genomic interval linked to mobilization by RNA interference. We will also analyze the function of the locus/gene in trans-endothelial migration and adhesion of HSPCs. Finally, using congenic animals in competitive transplantation/mobilization assays, we will analyze the correlation between mobilization proficiency and trafficking of HSPCs to either non-hematopoietic niches, e.g. to muscle tissue, or to other hematopoietic niches.