ST6Gal Sialyltransferase in Innate and Adaptive Immune Response

描述（由申请人提供）：炎症是最直接的血液学反应，是抵御入侵微生物的第一道防线。它还会引发一系列事件，导致更持久的适应性免疫。血液淤积的维持是至关重要的，过度的炎症会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，宿主对这些恶性肿瘤的反应与伤口愈合中的炎症的传统范式相似。ST6Gal-1唾液基转移酶的上调是全身性炎症反应的一个组成部分，在炎症病理中唾液基化状态升高具有潜在的诊断价值。然而，ST6Gal-1在炎症过程中的作用尚不清楚。我们的初步数据证明了ST6Gal-1在骨髓形成、中性粒细胞边缘/边界和急性中性粒细胞炎症方面的新贡献。由于ST6Gal-1缺乏，腹膜白细胞在感染因子和无菌刺激物的刺激下增加，这一事实表明ST6Gal-1在急性炎症中的内在作用。使用肾上腺素激发诱导边界的实验表明，ST6Gal-1缺乏时，边缘中性粒细胞池显着扩大。ST6Gal-1缺陷小鼠从环磷酰胺诱导的骨髓抑制中恢复的能力也显著增强。通过构建一个缺失P1 （Siat1deltaP1）的突变小鼠，P1是调节ST6Gal-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ST6Gal-1的需求是由P1启动子介导的。我们假设ST6Gal-1，可能是通过末端糖基结构的α 2,6-唾液修饰，在炎症细胞功能和维持血液停滞中起调节作用。我们将阐明ST6Gal-1如何以及在多大程度上调节这些过程的机制基础，通过确定1)炎症细胞功能影响ST6Gal-1缺陷的具体方式，2)P1启动子在发育和细胞范围内的利用，3)ST6Gal-1表达对炎症细胞功能的重要作用，以及4)当ST6Gal-1缺陷时，唾液聚糖结构如何改变，以及这种改变如何影响功能。这些研究将增加我们对ST6Gal-1如何调节循环中性粒细胞数量和功能的理解。这些研究也将揭示ST6Gal-1在细胞毒性抗肿瘤治疗后化疗恢复中的作用。

DESCRIPTION (provided by applicant): 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 myelopoesis, 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 recover from cyclophosphamide-induced myelosuppression. By constructing a mutant mouse with a deletion in P1 (Siat1deltaP1), 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 alpha2,6-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 recovery from chemotherapy following cytotoxic antineoplastic therapy.