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，目前尚不清楚其分子水平和生理学意义。值得注意的是，人类和小鼠动员造血干细胞和祖细胞（HSPCs）的能力存在显著的个体间差异和品系间差异。这表明有遗传调节动员。在鼠系统中，染色体11上的基因座与粒细胞集落刺激因子（G-CSF）诱导的干细胞动员能力的菌株间变异相关。调控这种变异的基因可能在HSPCs的定位和运输中起重要作用。随着对基于造血干细胞的疗法的临床需求不断增长，理解干细胞定位、动员和运输的生理调节将是重要的。该提案旨在通过产生亚同源动物鉴定11号染色体上的基因，该基因是HSPC动员的生理调节因子，随后通过RNA干扰对与动员相关的基因组间隔中的单个基因进行功能分析。我们还将分析该位点/基因在HSPCs跨内皮迁移和粘附中的功能。最后，在竞争性移植/动员试验中使用同源动物，我们将分析动员能力与HSPC向非造血小生境（例如肌肉组织）或其他造血小生境的运输之间的相关性。

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.