Probing the role of heparanase via in situ labeling

摘要 硫酸乙酰肝素蛋白多聚糖(HSPGs)，细胞外基质(ECM)的主要成分 所有组织类型，参与ECM的结构完整性，并通过 与细胞外基质成分和蛋白质配体结合，如生长因子和趋化因子。 乙酰肝素酶，是已知的唯一能切割硫酸乙酰肝素(HS)侧链的酶 HSPGs调节许多细胞过程，包括细胞外基质重塑和细胞内稳态- 结合HS，它控制附着在HS上的分子的生物利用度和活性。我们 假设乙酰肝素酶以编程方式切割HS侧链--某些HS 裂解导致细胞扩散，而其他特定HS结构的裂解负责 特定信号分子的释放，或热休克蛋白G的内稳态。我们的长期目标是 明确乙酰肝素酶在各种病理条件下的确切作用。当前的研究 重点是开发一套可以可视化时空的分子工具 肝素酶在活细胞和动物模型中的活性。这些结构上定义的探测器 结合原位标记策略以保留乙酰肝素酶作用部位的读出信号以 达到较高的空间分辨率和精度。我们将使用这些分子探测器来测试我们的 在癌症模型中的假说，并研究乙酰肝素酶在结构上确定的作用 体外和体内ECM重塑的分子成像研究。 好了！

Abstract Heparan sulfate proteoglycans (HSPGs), major components in the extracellular matrix (ECM) of all tissue types, participate in structural integrity of ECM and regulate cellular signaling via binding with ECM components and protein ligands such as growth factors and chemokines. Heparanase, the only known enzyme that can cleave the heparan sulfate (HS) side chains of HSPGs, regulates many cellular processes including ECM remodeling and homeostasis of cell- associated HS, and it controls the bioavailability and activity of molecules attached to HS. We hypothesize that heparanase cleaves HS side chains in a programmed manner – certain HS cleavage leads to cell dissemination, while cleavage of other specific HS structures is in charge of release of specific signaling molecules, or homeostasis of HSPGs. Our long term goal is to define the precise role of heparanase in various pathological conditions. The current research focuses on the development of a set of molecular tools that can visualize spatiotemporal activities of heparanase in both live cells and animal models. These structurally defined probes incorporate in situ labeling strategy to retain the readout signals at site of heparanase action to achieve high spatial resolution and precision. We will use these molecular probes to test our hypothesis in cancer models, and to study the structurally defined role of heparanase during ECM remodeling using molecular imaging both in vitro and in vivo. !