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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) 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。乙酰肝素酶，唯一已知可以裂解硫酸乙酰肝素 (HS) 侧链的酶 HSPG 调节许多细胞过程，包括 ECM 重塑和细胞稳态与 HS 相关，并且它控制与 HS 相连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裂解 HS 侧链 – 某些 HS 裂解导致细胞扩散，而其他特定 HS 结构的裂解则负责特定信号分子的释放或 HSPG 的稳态。我们的长期目标是定义乙酰肝素酶在各种病理条件下的精确作用。目前的研究专注于开发一套可以可视化时空的分子工具活细胞和动物模型中乙酰肝素酶的活性。这些结构定义的探针结合原位标记策略以保留乙酰肝素酶作用位点的读出信号实现高空间分辨率和精度。我们将使用这些分子探针来测试我们的癌症模型中的假设，并研究乙酰肝素酶在癌症过程中的结构定义作用使用体外和体内分子成像进行 ECM 重塑。！