Probing the role of heparanase via in situ labeling

通过原位标记探讨乙酰肝素酶的作用

基本信息

批准号：
10217185
负责人：
Lina Cui
金额：
$ 37.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

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. !

抽象的硫酸乙酰肝素蛋白聚糖（HSPG），细胞外基质（ECM）中的主要成分所有组织类型，参与ECM的结构完整性并通过与ECM成分和蛋白质配体（例如生长因子和趋化因子）结合。肝素酶，唯一可以清除硫酸乙酰肝素（HS）侧链的已知酶 HSPG，调节许多细胞过程，包括ECM重塑和细胞稳态相关的HS，它控制着附着在HS上的分子的生物利用度和活性。我们假设乙酰肝素以编程的方式切割HS侧链 - 某些HS 切割导致细胞传播，而其他特定HS结构的裂解为负责特定信号分子或HSPG的稳态的释放。我们的长期目标是定义肝素酶在各种病理条件下的精确作用。当前的研究专注于可以可视化时空的一组分子工具的开发肝素酶在活细胞和动物模型中的活性。这些结构定义的问题并入原位标签策略，以保留肝素酶动作现场的读数信号实现高空间分辨率和精度。我们将使用这些分子问题来测试我们的癌症模型中的假设，并研究肝素酶在期间的结构定义的作用 ECM在体外和体内都使用分子成像进行重塑。呢