ST6Gal Sialyltransferase in Innate and Adaptive Immune Response

炎症是最直接的血液反应，是抵御入侵的第一道防线。 微生物。它还启动了一系列事件，导致更持久的适应性免疫。维护 血液淤滞是至关重要的，过度的炎症可能会导致对自我的破坏性攻击。 未解决的炎症也会使宿主容易患上某些形式的癌症，而宿主对 这些恶性肿瘤与传统的伤口愈合过程中的炎症模式相似。向上- 调节ST6Gal-1唾液酸基转移酶是全身炎症反应的组成部分，并且 唾液酸化状态升高在炎症病理中有潜在的诊断价值。然而， ST6Gal-1在炎症过程中的作用仍然难以捉摸。 我们的初步数据显示ST6Gal-1与骨髓生成、中性粒细胞有关的新贡献 边缘/脱髓鞘和急性中性粒细胞炎症。事实上，腹膜白细胞增多症是 用感染剂和无菌刺激物攻击ST6Gal-1缺乏点后增加 ST6Gal-1在急性炎症中的内在作用。使用肾上腺素激发的实验 脱髓鞘实验显示ST6Gal-1上的中性粒细胞池明显扩大 缺乏症。ST6Gal-1缺陷小鼠的恢复能力也显著增强 环磷酰胺引起的骨髓抑制。通过构建P1中缺失的突变小鼠 (Siat1kP‘)，这是调节ST6Gal-1基因表达的六个主要启动子之一。 ST6Gal-1对炎症细胞功能的要求是由P1启动子介导的。 我们假设ST6Gal-1，可能是通过末端多糖结构的2，6-唾液酸基修饰， 在炎症细胞功能和维持血液学停滞方面起调节作用。我们会 阐明ST6Gal-1如何以及在多大程度上调节这些过程的机制基础 确定1)炎症细胞功能对ST6Gal-1缺乏的具体影响方式，2) P1启动子的发育和细胞利用范围，3)ST6Gal-1表达 对炎症细胞功能很重要，以及4)当ST6Gal-1被 不足，以及这种改变可能如何影响功能。这些研究将增加我们对 ST6Gal-1如何调节循环中性粒细胞的数量和功能。这些研究也将揭示 ST6Gal-1在细胞毒抗肿瘤治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.