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

• 批准号: 9382459
• 负责人: Lina Cui
• 金额: $ 37.84万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382459
• 关键词: Animal Model; Binding; Biological Availability; Cancer Model; Cell model; Cell physiology; Cells; Charge; Cleaved cell; Development; Diagnostic; Disease; Enzymes; Extracellular Matrix; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Homeostasis; In Situ; In Vitro; Inflammatory; Label; Ligands; Molecular; Molecular Probes; Pathologic; Proteins; Research; Resolution; Role; Side; Signal Transduction; Signaling Molecule; Site; Structure; Testing; Therapeutic; Tissues; chemokine; clinically significant; design; heparanase; in vivo; molecular imaging; spatiotemporal; tool; tumor progression

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。 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 我们的长期目标是释放特定信号分子或 HSPG 的稳态。 定义乙酰肝素酶在各种病理条件下的精确作用。 专注于开发一套可以可视化时空的分子工具 这些结构明确的探针在活细胞和动物模型中的活性。 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 我们将使用这些分子探针来测试我们的空间分辨率和精度。 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。 ！