Effects of direct pharmacological Gq protein modulation on lung and right heart remodeling

G蛋白是许多器官系统中(病理)生理功能的重要调节器。在肺中，Gq亚型具有特别的相关性，因为它是呼吸道和肺动脉中平滑肌张力的关键调节因子。该信号通路也参与慢性肺部疾病，如哮喘和肺动脉高压。因此，选择性的PAN-GQ抑制剂将有助于更好地了解GQ蛋白的(病理)生理作用，甚至可能提供新的治疗选择。在目前的提案中，我们将研究由该联盟提供的药理GQ抑制剂FR900359对其降低肺内气道和血管张力的潜力的影响。为此，我们将在小鼠和小鼠、猪和人类组织中寻求体外、体外和体内的方法。我们将比较药物GQ抑制剂对呼吸道和血管功能的影响，以及对遗传性GQ缺陷细胞和组织的影响，以从机制上了解GQ亚型的个体生理作用。最后，我们将研究药物GQ抑制剂在哮喘和肺动脉高压小鼠模型中降低气道和血管张力的潜力。我们还将测试不同的应用途径，如吸入该化合物，以最大限度地减少体内的全身副作用。因此，我们的研究有望为GQ蛋白在肺内音调调节中的机制作用以及GQ蛋白抑制在肺部疾病中的治疗潜力提供新的见解。

G proteins are important modulators of (patho-)physiological functions in many organ systems. In the lung, the Gq subtype is of particular relevance, as it is a key mediator of smooth muscle tone in both, airways and pulmonary arteries. This signaling pathway is also involved in chronic lung diseases such as asthma and pulmonary hypertension. Therefore a selective pan-Gq inhibitor would help to gain better insight into the (patho-)physiological role of Gq proteins and could even provide novel therapeutic options. In the current proposal we will investigate the effect of the pharmacological Gq inhibitor FR900359 provided by the consortium in regard to its potential to reduce airway and vascular tone in the lung. To this end we will pursue in vitro, ex vivo and in vivo approaches in mouse and murine, porcine and human tissue. We will compare the effects of the pharmacological Gq inhibitor on airway and vessel function with that in cells and tissues of genetic Gq deficiency in order to mechanistically understand the individual physiological role of Gq subtypes. Finally, we will examine the potential of the pharmacological Gq inhibitor to reduce airway and vascular tone in mouse models of asthma and pulmonary hypertension. We will also test different application routes such as inhalation of the compound to minimize systemic side effects in vivo. Thus, our studies are expected to provide novel insights into the mechanistic role of Gq proteins in tone regulation in the lung and into the therapeutic potential of Gq protein inhibition in lung disease.