Phosphodiesterase 1 signalsomes: the utility of peptide disruptors for pulmonary arterial hypertension

磷酸二酯酶 1 信号体：肽干扰物在肺动脉高压中的应用

• 批准号: 2884866
• 金额: --
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2884866
• 关键词: Phosphodiesterase; signalsomes; utility; peptide; disruptors

The ubiquitously expressed second messenger, cyclic AMP (cAMP), plays a key role in controlling cellular responses that regulate a wide number of physiological processes throughout the body. Compartmentalization of cAMP is key in the spatio-temporal control of cAMP dynamics that determines its function in cells. Phosphodiesterases (PDEs), which hydrolyse cAMP, underpin compartmentalization of the second messenger by forming specific protein complexes (signalsomes) that restrict cAMP within subcellular compartments. Such protein complexes also include membrane-bound proteins (G protein-coupled receptors), scaffolding proteins (A kinase anchoring proteins) and downstream mediators (protein kinase A) of cAMP. Identification of PDE signalsomes has uncovered PDE-specific protein complexes, many of which are implicated in heart failure, cancer and cognitive decline. Mapping of PDE-protein interfaces and the rational design of novel peptide disrupters has uncovered the role of such complexes in cell function. Cell permeable peptide disrupters, which have higher target specificity to traditional small molecules, represent an exciting area of drug discovery. We have shown a specific PDE family member, PDE1C, plays a pivotal role in shaping cAMP gradients in pulmonary artery smooth muscle cells (PASMCs) and its increased expression and activity accounts for lower cAMP and increased PASMC proliferation in pulmonary arterial hypertension (PAH, Murray et al., 2007). More recently we find PDE1C limits the efficacy of prostacyclin analogues, which are currently clinically approved for PAH, by interacting with the prostacyclin (IP) receptor and enhancing its degradation. Using a variety of molecular and biochemical approaches together with 'peptide chip' technology (Professor Baillie, Blair et al., 2019), this project aims to define the interacting proteins, subcellular localisation and function of this exciting newly discovered PDE1C/IP signalsome. Furthermore, we will develop novel peptide disruptors, including cell permeable cyclic peptides (Dr Houssen, Idress et al., 2020) using synthetic biology and chemistry, to elucidate the functional significance of the PDE1C/IP complex in PASMC and its role in PAH. This PhD project brings together areas of expertise in pulmonary physiology, pharmacology, biochemistry, synthetic biology and chemistry from the University of Aberdeen and University of Glasgow, which will offer an optimal training environment and provide the student with a set of highly desirable skills. It is expected that completion of the aims will advance our understanding of the cellular function of PDE1 signalsomes and uncover novel peptide therapeutics for diseases.

普遍表达的第二信使环腺苷酸（cAMP）在控制细胞反应中起着关键作用，细胞反应调节整个身体的许多生理过程。cAMP的区室化是决定其在细胞中的功能的cAMP动力学的时空控制的关键。磷酸二酯酶（PDE）水解cAMP，通过形成特异性蛋白质复合物（信号体）将cAMP限制在亚细胞区室中，从而支持第二信使的区室化。此类蛋白质复合物还包括膜结合蛋白（G蛋白偶联受体）、支架蛋白（A激酶锚定蛋白）和cAMP的下游介质（蛋白激酶A）。PDE信号体的鉴定揭示了PDE特异性蛋白复合物，其中许多与心力衰竭，癌症和认知能力下降有关。PDE-蛋白质界面的映射和新型肽破坏剂的合理设计揭示了这种复合物在细胞功能中的作用。细胞渗透性肽破坏剂对传统小分子具有更高的靶向特异性，代表了药物发现的一个令人兴奋的领域。我们已经表明，特定PDE家族成员PDE 1C在形成肺动脉平滑肌细胞（PASMC）中的cAMP梯度中起关键作用，并且其增加的表达和活性解释了肺动脉高压中较低的cAMP和增加的PASMC增殖（PAH，Murray等人，2007年）。最近，我们发现PDE 1C通过与前列环素（IP）受体相互作用并增强其降解，限制了目前临床上批准用于PAH的前列环素类似物的疗效。使用各种分子和生物化学方法以及“肽芯片”技术（Baillie教授，Blair等人，2019年），该项目旨在定义这种令人兴奋的新发现的PDE 1C/IP信号体的相互作用蛋白，亚细胞定位和功能。此外，我们将开发新的肽破坏剂，包括细胞可渗透的环肽（Dr胡森，Idress et al.，2020）使用合成生物学和化学，阐明PDE 1C/IP复合物在PASMC中的功能意义及其在PAH中的作用。这个博士项目汇集了来自阿伯丁大学和格拉斯哥大学的肺生理学，药理学，生物化学，合成生物学和化学方面的专业知识，这将提供最佳的培训环境，并为学生提供一套非常理想的技能。预计这些目标的完成将促进我们对PDE 1信号体细胞功能的理解，并发现新的疾病肽治疗方法。