Heparan Sulfate-TLR in Health, Injury and Immunity

对多细胞生物体健康的许多传染性和有害挑战是由 保护性免疫反应。保护性免疫的一些方面是结构性的，而另一些方面是诱导的 当外来生物或其产品与称为Toll样受体的特殊受体相互作用时， 免疫细胞和炎症细胞。这一概念可能完全解释了对 产生内毒素等刺激分子的细菌生物体，但无法解释 对于不能产生外源性激动剂的病毒、某些毒素、肿瘤或移植，免疫力会提高。 当其他人和我们最近证明了某些内源性 糖类可以通过Toll样受体刺激细胞。这些糖类，硫酸乙酰肝素的碎片 蛋白多糖和透明质酸，是在炎症和组织损伤过程中产生的，因此提供 对生物体健康的威胁与先天免疫和获得性免疫的唤醒之间的关键联系 回应。因为Toll样受体的一些内源性激活剂是Toll样受体的切割产物 组织的组成部分，推测Toll样受体可能在感觉两者中起更广泛的作用 健康状况和潜在危害状况。本申请中提出的研究将 确定硫酸乙酰肝素与苦参素样受体相互作用的方式。这项工作将决定如何 硫酸乙酰肝素与受体结合，产生信号并引起生物反应。 这一目标将通过小鼠细胞来实现，小鼠细胞表达正常或突变的Toll样受体和 诱导受体表达的细胞。这项研究还将阐明Toll样受体如何相互作用 在正常的静息条件下与硫酸乙酰肝素蛋白多糖结合，在 感受器会受到刺激。这项研究将确定Toll样受体在这一代中的功能 T细胞非依赖和T细胞依赖的B细胞应答。

Many infectious and noxious challenges to the well being of multi-cellular organisms are controlled by protective immune responses. Some facets of protective immunity are constitutive while some are induced when foreign organisms or their products interact with specialized receptors, called toll-like receptors, on immune and inflammatory cells. This concept may account completely for the arousal of immunity to bacterial organisms that produce stimulatory molecules such lipopolysaccharide but fails to account for how immunity is raised against viruses, certain toxins, tumors or transplants that fail to produce extrinsic agonists. This limitation was overcome when others and we recently demonstrated that certain endogenous saccharides can stimulate cells via toll-like receptors. These saccharides, fragments of heparan sulfate proteoglycan and hyaluronic acid, are generated in course of inflammation and tissue injury and thus provide a critical link between threats to the well being of the organism and arousal of innate and adaptive immune responses. Because some endogenous activators of toll-like receptors are the cleavage products of components of tissues, it is postulated that the toll like receptors may function more broadly in sensing both conditions of well being and conditions of potential harm. The research proposed in this application will determine the means by which heparan sulfate interacts with toil-like receptors. The work will determine how heparan sulfate associates with the receptors, generates a signal and gives rise to a biological response. This objective will be addressed using murine cells, which express normal or mutant toll-like receptors and cells in which receptor expression is induced. The research will also elucidate how toll-like receptors interact with heparan sulfate proteoglycan in the normal, resting conditions and end in conditions in which the receptors become stimulated. The research will determine how toll-like receptors function in the generation of T cell independent and T cell dependent B cell responses.