ST6Gal Sialyltransferase in Innate and Adaptive Immune Response

炎症是最直接的血液学反应，是抵抗入侵的第一道防线。 微生物它还启动级联事件，导致更持久的适应性免疫。维护 血液淤滞是关键的，并且过度炎症可导致对自身的破坏性攻击。 未解决的炎症也可能使宿主易患某些形式的癌症，并且宿主对癌症的反应可能会降低。 这些恶性肿瘤显示出与伤口愈合中的炎症的传统范例相似。向上- ST 6 Gal-1唾液酸转移酶的调节是全身炎症反应的组成部分， 在炎性病理中唾液酸化状态升高具有潜在的诊断价值。但 ST 6 Gal-1在炎症过程中的作用仍然是难以捉摸的。 我们的初步数据表明，ST 6 Gal-1与骨髓增生异常综合征、中性粒细胞增多症、 边集/去边集和急性嗜中性炎症。事实上，腹膜白细胞增多症 在ST 6 Gal-1缺陷点用感染剂和无菌刺激物攻毒后增加 ST 6 Gal-1在急性炎症中的内在作用。使用肾上腺素激发的实验 去边缘化证实了在ST 6 Gal-1作用下，有边缘的中性粒细胞池显著扩大 缺陷ST 6 Gal-1缺陷小鼠也具有显著增强的恢复能力， 环磷酰胺引起的骨髓抑制通过构建P1基因缺失的突变小鼠， （Siat 1 kP 1），调节ST 6 Gal-1基因表达的六个主要启动子之一，我们证明了 炎症细胞功能对ST 6 Gal-1的需求是由P1启动子介导的。 我们假设ST 6 Gal-1可能通过末端聚糖结构的α 2，6-唾液酸修饰， 作为炎症细胞功能和维持血液停滞的调节剂。我们将 阐明这些过程如何以及在何种程度上被ST 6 Gal-1通过以下方式调节的机制基础： 确定1）炎性细胞功能性影响ST 6 Gal-1缺陷的具体方式，2） P1启动子的发育和细胞利用范围，3）其中ST 6 Gal-1表达是 重要的炎症细胞功能，和4）如何唾液酸聚糖结构改变时，ST 6 Gal-1是 以及这些变化如何影响功能。这些研究将增加我们对 ST 6 Gal-1如何调节循环中性粒细胞数量和功能。这些研究还将揭示 ST 6 Gal-1在介导细胞毒性化疗后化疗恢复中的作用。

Inflammation, the most immediate hematologic response, is the first line of defense against invading microbes. It also initiates the cascade of events leading to longer lasting adaptive immunity. Maintenance of hematologic stasis is critical, and excessive inflammation can lead to destructive attacks against self. Unresolved inflammation can also predispose the host to some forms of cancers, and the host response to these malignancies show parallels to the traditional paradigms of inflammation in wound healing. Up- regulation of the ST6Gal-1 sialyltransferase is an integral part of the systemic inflammatory response, and there is potential diagnostic value for elevated sialylation status in inflammatory pathologies. However, the contribution of ST6Gal-1 in the inflammatory process remains elusive. Our Preliminary Data demonstrate novel contributions for ST6Gal-1 related to myelopoissis, neutrophil margination/demargination, and acute neutrophilic inflammation. The fact that peritoneal leukocytosis was increased following challenge with an infectious agent and a sterile irritant upon ST6Gal-1 deficiency points to an intrinsic role of ST6Gal-1 in acute inflammation. Experiments using epinephrine challenge to elicit demargination demonstrated a significantly expanded pool of marginated neutrophils upon ST6Gal-1 deficiency. ST6Gal-1 deficient mice also had a strikingly enhanced capacity to recoverfrom cyclophosphamide-induced myelosuppression. By constructing a mutant mouse with a deletion in P1 (Siat1kP'\), one of six major promoters regulating expression of the ST6Gal-1 gene, we demonstrated the requirement for ST6Gal-1 for inflammatory cell functionality is mediated by the P1 promoter. We hypothesize that ST6Gal-1, presumably by a2,6-sialyl modifications of terminal glycan structures, serves as a regulator in inflammatory cell functionality and in maintenance of hematologic stasis. We shall elucidate the mechanistic basis of how, and to what extent these processes are modulated by ST6Gal-1 by determining 1) the specific ways inflammatory cell functionality impacted upon ST6Gal-1 deficiency, 2) the developmental- and cellular-range of utilization of the P1 promoter, 3) where ST6Gal-1 expression is important for inflammatory cell function, and 4) how the sialyl-glycan architecture is altered when ST6Gal-1 is deficient, and how such alterations may impact on function. These studies will increase our understanding of how ST6Gal-1 modulates circulating neutrophil number and function. These studies will also shed light on the role of ST6Gal-1 in mediating recoveryfrom chemotherapy following cytotoxic antineoplastic therapy.