Genetic Reg. of Hematopoietic Stem Cell Mobilization

造血干细胞和祖细胞（HSPCs）从骨髓向外周血的动员是一种生物学现象，在分子水平上尚不清楚，其生理学重要性也知之甚少。值得注意的是，人类和小鼠在动员造血干细胞和祖细胞（HSPCs）的能力上存在显著的个体间差异和品系间差异，这表明存在动员的遗传调控。在小鼠系统中，11号染色体上的一个位点与粒细胞集落刺激因子（G-CSF）诱导的干细胞动员能力的株间变异有关。调节这种变异的基因可能在造血干细胞的定位和贩运中起重要作用。随着临床对造血干细胞治疗的需求日益增长，了解干细胞定位、动员和运输的生理调节将变得非常重要。本研究旨在通过产生亚同源动物来鉴定11号染色体上的HSPC动员生理调节基因，并随后对基因组间隔中与RNA干扰动员相关的单个基因进行功能分析。我们还将分析位点/基因在HSPCs跨内皮迁移和粘附中的功能。最后，使用同源动物进行竞争性移植/动员实验，我们将分析动员能力与HSPCs转移到非造血生态位（如肌肉组织）或其他造血生态位之间的相关性。

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.