Unveiling the role of G-protein-coupled receptors in Pulmonary Hypertension

揭示 G 蛋白偶联受体在肺动脉高压中的作用

• 批准号: 515358308
• 负责人: Professor Dr. Ralph Schermuly
• 金额: --
• 依托单位: Biomedizinisches Forschungszentrum Seltersberg (BFS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515358308?language=en
• 关键词: Unveiling; role; protein; coupled; receptors

Unveiling the role of the G protein-coupled receptors GPRC5B, P2Y2, GPR4, and GPR21 in the development and treatment of pulmonary hypertension. G-protein coupled receptors (GPCRs) play a prominent role in the therapy of cardiopulmonary diseases and, with over 1000 different members, represent the largest protein superfamily. Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vessels that alters all vascular layers and increases the pulmonary artery pressure (PAP) leading in late stages, if not treated, to the right heart failure and consequently the death. Numerous drugs have been developed in the past to act as agonists or antagonists of GPPCRs in PAH. In initial studies on human cells and tissues from PAH patients, we identified new differentially regulated GPCRs, the role of which is to be further investigated in this application. Using GPCR-specific microarrays and sequencing studies, we identified four new GPCRs (GPRC5B, GPR4, GPR21, and P2Y2) and three G proteins (GNA11, GNA14, and GNG2) that are significantly changed in patients and yet have not been investigated in PAH research. So far, we have carried out our initial studies on the role of the purinergic receptor P2Y2 in human pulmonary arterial endothelial and smooth muscle cells (HPAECs or HPASMCs). The endothelial P2Y2 receptor is involved in increased NO secretion, whereas the activation of P2Y2 in the pulmonary smooth muscle cells with its specific agonist (MRS2768) attenuates the proliferation rate of the IPAH-HPASMCs and should be therefore further investigated. The function of the receptors GPRC5B, GPR4, and GPR21 has only recently been demonstrated and their specific ligands, which have not yet been investigated in the field of pulmonary hypertension, are available for further investigations (compound 3b and GRA2). The four promising GPCRs and their ligands (GPRC5B without ligands, GPR4 and its compound 3b, GPR21 and its ligand GRA2 as well as P2Y2 and its ligand MRS2768) in addition to GNA11, GNA14, and their ligands (FR900359, YM-254890, and WU-07047) will be investigated in invitro and ex-vivo (isolated intrapulmonary arterial rings, isolated perfused mouse lungs). The in-vivo approach will consider endothelial- and smooth muscle-specific induced knockout mice of P2Y2 and GPRC5B to figure out their role in the different cell layers of pulmonary vessels. In summary, due to our best knowledge, this study would be the first comprehensive study for PAH-G proteins and PAH-GPCRs towards more understanding, better conditions, and new treatment for PAH patients.

揭示G蛋白偶联受体GPRC5B、P2Y2、GPR4和GPR21在肺动脉高压发生和治疗中的作用。g蛋白偶联受体（gpcr）在心肺疾病的治疗中发挥着重要作用，是最大的蛋白质超家族，有超过1000个不同的成员。肺动脉高压（PAH）是一种肺血管疾病，它改变了所有的血管层，增加了肺动脉压（PAP），如果不治疗，在晚期会导致右心衰，最终导致死亡。过去已经开发了许多药物作为PAH中GPPCRs的激动剂或拮抗剂。在对PAH患者的人体细胞和组织的初步研究中，我们发现了新的差异调节的gpcr，其作用有待进一步研究。通过gpcr特异性微阵列和测序研究，我们发现了四种新的gpcr （GPRC5B、GPR4、GPR21和P2Y2）和三种G蛋白（GNA11、GNA14和GNG2），这些蛋白在患者中发生了显著变化，但尚未在PAH研究中进行研究。到目前为止，我们对嘌呤能受体P2Y2在人肺动脉内皮细胞和平滑肌细胞（HPAECs或HPASMCs）中的作用进行了初步研究。内皮细胞P2Y2受体参与了NO分泌的增加，而P2Y2在肺平滑肌细胞中的激活及其特异性激动剂（MRS2768）可降低IPAH-HPASMCs的增殖率，因此应进一步研究。受体GPRC5B、GPR4和GPR21的功能直到最近才被证实，它们的特异性配体（化合物3b和GRA2）在肺动脉高压领域尚未被研究，可用于进一步研究。除了GNA11、GNA14及其配体（FR900359、YM-254890和wu07047）外，我们还将在体外和离体（分离的肺内动脉环、分离的灌注小鼠肺）研究四种有前景的gprcrs及其配体（不含配体的GPRC5B、GPR4及其化合物3b、GPR21及其配体GRA2以及P2Y2及其配体MRS2768）。体内方法将考虑内皮和平滑肌特异性诱导P2Y2和GPRC5B基因敲除小鼠，以了解它们在肺血管不同细胞层中的作用。综上所述，本研究将是首个针对PAH- g蛋白和PAH- gpcr的全面研究，旨在更好地了解PAH患者，改善病情，寻找新的治疗方法。