ST6Gal I sialyltransferase in hematopoiesis

描述（由申请人提供）：调节造血和维持造血平衡的能力对生物体的福利至关重要，无论是满足对抗入侵病原体的额外需求，还是在骨髓消融事件后重建造血室。衰老伴随着造血能力的普遍下降，导致对感染和自身免疫性疾病的易感性增加。造血室整体维持的一个关键参数是造血干细胞和祖细胞（HSPCs）在适当的支持性骨髓壁龛中的驻留。唾液化聚糖参与多种细胞粘附过程，影响免疫和运输的多个方面；然而，对聚糖在早期造血过程中所起的作用知之甚少。我们的实验室最近发现了唾液基转移酶ST6Gal-1在调节HSPC增殖中的一种新的生物学功能。有令人信服的证据表明，细胞外ST6Gal-1可以通过不同于典型的ER/高尔基途径的糖基化途径重塑HSPC表面。这些数据指向了一个新的概念，即从远端来源产生的细胞外糖基转移酶可以作为调节造血的“系统因素”，推测是通过对HSPC表面成分的细胞外或外源性唾液修饰。有4个具体目标。首先是通过使用仅在ST6Gal-1表达方式上存在差异的小鼠品系，评估骨髓造血室中ST6Gal-1表达失调的影响。第二个目的是评估ST6Gal-1的外在途径和典型的ER/高尔基途径在造血细胞表面唾液化中的相对贡献，最终目的是确定外在ST6Gal-1作用的靶分子。通过分析静态和纯粹流动条件下hspc -基质粘附以及ST6Gal-1对细胞内信号通路的影响，hspc受ST6Gal-1调控的机制将成为Aim 3的重点。目的4将评估ST6Gal-1表达失调对造血能力的长期影响。本项目的总体目标是了解ST6Gal-1在维持造血功能中的准确作用和机制，最终提出有效修饰造血功能的聚糖工程策略。

DESCRIPTION (provided by applicant): The ability to regulate hematopoiesis and to maintain hematopoietic balance is critical to the welfare of an organism, whether it is to meet additional demands to combat invading pathogens, or to re-establish the hematopoietic compartment subsequent to myelo-ablative events. Aging is accompanied by a general decline in hematopoietic capabilities, contributing to an increasing susceptibility to infections and to autoimmune conditions. A key parameter in the overall maintenance of the hematopoietic compartment is the residency of hematopoietic stem and progenitor cells (HSPCs) in the appropriate supportive marrow niches. Sialylated glycans participate in diverse cellular adhesive processes impacting multiple aspects of immunity and trafficking; however, little is known of the roles glycans play in early hematopoietic processes. Our laboratory has recently uncovered a novel biologic function for the sialyltransferase, ST6Gal-1, in the regulation of HSPC proliferation. There is compelling evidence that HSPC surfaces can be remodeled by extracellular ST6Gal-1, in a glycosylation pathway divergent from the canonical ER/Golgi-based pathway. The data point to the novel concept that extracellular glycosyltransferases generated from distal sources can function as "systemic factors" in regulating hematopoiesis, putatively by the extracellular or extrinsic sialyl-modification of HSPC surface components. There are 4 Specific Aims. The first is to evaluate the impact of dysregulated ST6Gal-1 expression in the bone marrow hematopoietic compartment through the use of mice strains that differ only in the way they express ST6Gal-1. The second aim is to evaluate the relative contributions of the extrinsic and the canonical ER/Golgi-based pathways of ST6Gal-1 in sialylation of hematopoietic cell surfaces, with the ultimate aim of identifying the target molecules of extrinsic ST6Gal-1 action. The mechanism by which HSPCs are regulated by ST6Gal-1 will be the focus of Aim 3, through analysis of HSPC-stroma adhesion under static and flow-sheer conditions, and ST6Gal-1 impact on intracellular signaling pathways. Aim 4 will evaluate the long-term impact of dysregulated ST6Gal-1 expression on hematopoietic capacities. The overall goal of this project is to understand the precise contribution and mechanism of ST6Gal-1 in the maintenance of hematopoietic functions, ultimately to yield glycan engineering strategies for effective modification of hematopoietic function. PUBLIC HEALTH RELEVANCE: Hematopoiesis is the process through which bone marrow stem cells continuously regenerate all blood cell lineages while simultaneously self-renewing to replenish the stem cell pool. Regulating hematopoiesis is critical for meeting additional demands to combat invading pathogens and maintaining hematopoietic equilibrium. Ageing is accompanied by a decline in hematopoietic capabilities, contributing to an increased susceptibility to infections and autoimmune conditions. We have recently uncovered an entirely novel hematopoietic regulation pathway, mediated by the sialyltransferase, ST6Gal-1. We hypothesize those extracellular ST6Gal-1 functions as a "systemic factor" in regulating hematopoietic stem and progenitor cell behavior, putatively by the extracellular modification of hematopoietic cell surfaces. The overall goal of this project is to understand the contribution and mechanism of ST6Gal-1 in the maintenance of hematopoietic functions, ultimately to yield new treatments that effectively modify hematopoietic function.