Heparan Sulfate-TLR in Health, Injury and Immunity

描述（由申请人提供）：许多对多细胞生物健康的传染性和毒性挑战是由保护性免疫反应控制的。保护性免疫的某些方面是构成性的，而当外来生物或其产物与免疫细胞和炎症细胞上的特殊受体（称为toll样受体）相互作用时，有些方面是诱导的。这一概念可以完全解释对产生刺激分子（如脂多糖）的细菌生物体的免疫唤起，但不能解释如何提高对不能产生外源性激动剂的病毒、某些毒素、肿瘤或移植的免疫。当我们和其他人最近证明某些内源性糖可以通过toll样受体刺激细胞时，这一限制被克服了。这些糖，硫酸肝素蛋白聚糖和透明质酸的片段，是在炎症和组织损伤过程中产生的，因此在对生物体健康的威胁和先天和适应性免疫反应的唤醒之间提供了关键的联系。由于toll样受体的一些内源性激活剂是组织成分的裂解产物，因此假设toll样受体在感知健康状况和潜在危害状况方面可能具有更广泛的功能。本应用中提出的研究将确定硫酸肝素与劳样受体相互作用的方法。这项工作将确定硫酸肝素如何与受体结合，产生信号并引起生物反应。这一目标将通过表达正常或突变toll样受体的小鼠细胞和诱导受体表达的细胞来实现。该研究还将阐明toll样受体如何在正常的静息条件下与硫酸肝素蛋白聚糖相互作用，并在受体受到刺激的条件下结束。该研究将确定toll样受体如何在T细胞非依赖性和T细胞依赖性B细胞反应的产生中起作用。

DESCRIPTION (provided by applicant): 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 could stimulate cells via toll-like receptors. These saccharides, fragments of heparan sulfate proteoglycans 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 proteoglycans 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.