Relaxin and its receptor RXFP1 in cell motility

我的研究项目已经建立了松弛素（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。这些肽诱导强大的组织蛋白酶、基质金属蛋白酶MMP14、MMP2、MMP抑制剂TIMP2和Ca2+结合蛋白S100A4的表达，促进ECM渗透并增强甲状腺细胞的运动性。我最近发现RLN2重塑了突出细胞膜的主要迁移边缘（称为伪足）的蛋白质组成，这为松弛素的研究开辟了新的令人兴奋的途径。在迁移前沿被松弛素富集的蛋白现在可以被定位，以了解RLN2-RXFP1系统在甲状腺细胞中的影响。RLN2通过S100A4等靶点激活Wnt通路影响甲状腺细胞运动，我将探讨RXFP1与Wnt信号之间的串扰。迁移细胞暴露于不断变化的微环境中，使细胞容易发生程序性细胞死亡（PCD）。我将利用新型3d纳米分辨率成像和其他先进的工具，探索我们在体内观察到的RXFP1信号的抗凋亡作用是否可以保护迁移细胞免受PCD的侵害。成功建立了新的cre-lox转基因（tg）小鼠品系，用于控制组织特异性激活组成活性突变体RXFP1，这将使我现在能够产生双tg小鼠，用于RXFP1的甲状腺特异性激活。然后通过诱导甲状腺功能低下和甲状腺功能亢进应激来刺激这些小鼠，并评估一致的RXFP1信号对甲状腺内分泌系统的影响。我独特的项目为RLN2-RXFP1在甲状腺中的作用提供了新的和独特的数据。我之前的数据显示，甲状腺中RLN2-RXFP1和INSL3-RXFP2具有明显的功能重叠。因此，这一建议很可能为甲状腺松弛素样配体受体系统提供新的重要数据。

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.