ST6Gal Sialyltransferase in Innate and Adaptive Immune Response

描述(申请人提供)：炎症，最直接的血液学反应，是抵御入侵微生物的第一道防线。它还启动了一系列事件，导致更持久的适应性免疫。维持血液停滞是至关重要的，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传统炎症模式相似。ST6Gal-1唾液酸化转移酶的上调是全身炎症反应的一个组成部分，在炎症病理中唾液酸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、中性粒细胞边际化/去髓质和急性中性粒细胞炎症有关。ST6Gal-1缺乏用感染剂和无菌刺激物攻击后，腹膜白细胞增多的事实表明ST6Gal-1在急性炎症中的内在作用。使用肾上腺素刺激来诱导脱精症的实验表明，ST6Gal-1缺乏时，边缘形成的中性粒细胞池显着扩大。ST6Gal-1基因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。通过构建一个在调节ST6Gal-1基因表达的六个主要启动子之一的P1(Siat1deltaP1)中缺失的突变小鼠，我们证明了ST6Gal-1对炎症细胞功能的需求是由P1启动子介导的。我们推测，ST6Gal-1可能通过α-2，6-唾液酸基修饰末端多聚糖结构，在炎症细胞功能和维持血液学停滞中发挥调节作用。我们将通过确定1)炎症细胞功能在ST6Gal-1缺乏时影响炎症细胞功能的具体方式，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的重要位置，以及4)当ST6Gal-1缺乏时唾液酸聚糖结构如何改变，以及这些改变可能如何影响功能，阐明ST6Gal-1如何以及在多大程度上调节这些过程的机制。这些研究将增加我们对ST6Gal-1如何调节循环中中性粒细胞数量和功能的理解。这些研究还将阐明ST6Gal-1在细胞毒性抗肿瘤治疗后介导化疗恢复中的作用。

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.