Relaxin and its receptor RXFP1 in cell motility

松弛素及其受体RXFP1在细胞运动中的作用

• 批准号: 342187-2011
• 负责人: Klonisch, Thomas
• 金额: $ 2.62万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=482448
• 关键词: Relaxin; its; receptor; RXFP1; cell

My research program has established relaxin (RLN2) and INSL3 and their cognate G protein coupled receptors, RXFP1 and RXFP2, as novel mediators of cell migration and extracellular matrix (ECM) degradation. These peptides induce the expression of powerful cathepsins, matrix-metalloproteinases MMP14, MMP2, and the MMP inhibitor TIMP2, and the Ca2+-binding protein S100A4 to facilitate ECM penetration and enhanced motility of thyroid cells. My recent discovery that RLN2 remodels the protein composition at the leading migrating edge of the protruding cell membrane, called pseudopodia, has opened new and exciting avenues in relaxin research. Proteins enriched by relaxin at the leading migrating edge can now be mapped to appreciate the impact of the RLN2-RXFP1 system in thyroid cells. Through targets like S100A4, RLN2 can activate the Wnt pathway to affect thyroid cell motility and I will explore the cross-talk between RXFP1 and Wnt signaling. Exposure of migrating cells to a changing micro-environment makes cells vulnerable to forms of programmed cell death (PCD). Employing novel 3D-nanoresolution imaging and other sophisticated tools available to me, I will explore if the anti-apoptotic actions of RXFP1 signaling we observed in-vivo can protect migrating cells against PCD. The successfully established new cre-lox transgenic (tg) mouse strain for the controlled tissue-specific activation of a constitutively active mutant RXFP1 will allow me now to generate double tg mice for thyroid-specific activation of RXFP1. These mice are then challenged by the induction of a hypothyroid and hyperthyroid stress and the effects of consistent RXFP1 signaling on thyroid endocrine system are evaluated. My unique program contributes new and unique data on the role of RLN2-RXFP1 in the thyroid. My previous data showed a significant functional overlap between the RLN2-RXFP1 and INSL3-RXFP2 in the thyroid. Thus, this proposal is likely to generate new and important data for both relaxin-like ligand-receptor systems in the thyroid.

我的研究项目已确定松弛素 (RLN2) 和 INSL3 及其同源 G 蛋白偶联受体 RXFP1 和 RXFP2 作为细胞迁移和细胞外基质 (ECM) 降解的新型介质。这些肽诱导强效组织蛋白酶、基质金属蛋白酶 MMP14、MMP2 和 MMP 抑制剂 TIMP2 以及 Ca2+ 结合蛋白 S100A4 的表达，以促进 ECM 渗透并增强甲状腺细胞的运动性。我最近发现 RLN2 重塑了突出细胞膜（称为伪足）的前导迁移边缘的蛋白质组成，这为松弛素研究开辟了新的、令人兴奋的途径。现在可以绘制由松弛素在迁移前缘富集的蛋白质，以了解 RLN2-RXFP1 系统对甲状腺细胞的影响。通过 S100A4 等靶点，RLN2 可以激活 Wnt 通路来影响甲状腺细胞运动，我将探讨 RXFP1 和 Wnt 信号传导之间的串扰。迁移细胞暴露于不断变化的微环境使细胞容易遭受程序性细胞死亡（PCD）的影响。利用新型 3D 纳米分辨率成像和其他可用的复杂工具，我将探索我们在体内观察到的 RXFP1 信号传导的抗凋亡作用是否可以保护迁移细胞免受 PCD 的侵害。成功建立的新的 cre-lox 转基因 (tg) 小鼠品系用于控制组织特异性激活组成型活性突变体 RXFP1，现在将使我能够生成双 tg 小鼠，用于甲状腺特异性激活 RXFP1。然后，这些小鼠受到诱导甲状腺功能减退和甲状腺功能亢进应激的挑战，并评估一致的 RXFP1 信号传导对甲状腺内分泌系统的影响。我独特的计划提供了有关 RLN2-RXFP1 在甲状腺中的作用的新的独特数据。我之前的数据显示甲状腺中 RLN2-RXFP1 和 INSL3-RXFP2 之间存在显着的功能重叠。因此，该提议可能会为甲状腺中的松弛素样配体受体系统产生新的重要数据。