cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.

cAMP 磷酸二酯酶-4：信号复合物、调节和潜在治疗靶点。

• 批准号: MR/J007412/1
• 负责人: George Baillie
• 金额: $ 62.81万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ007412%2F1
• 关键词: cAMP; phosphodiesterase; signalling; complexes; regulation

The death rate from respiratory diseases in the UK is twice the EU average and costs the NHS more than any other disease area. Chronic Obstructive Pulmonary Disease, the fourth leading cause of death in the world, causes around 26,000 deaths/year and asthma around 1500 deaths/yr in the UK. This debilitating illness is associated with lung damage caused by chronic inflammation due to the sustained activation of 'inflammatory' cells. Raising the levels of a substance called cAMP, inside these cells, can stop this. An effective way of doing this is to stop cAMP from being broken down by PDE4 enzymes. At the moment scientists have made inhibitor molecules that bind tightly to the 'mouth' on PDE4 where cAMP is digested, stopping it breaking down cAMP. However, a major problem using these as medicines are side-effects like nausea and vomiting. It's now clear that there is a large family of PDE4 enzymes where only certain of these are found in cells causing inflammation and damage in lungs. We aim to identify the particular PDE4 enzymes that it is important to inhibit in order to stop damage and help repair lungs. Then we need to devise ways to inhibit these selectively, rather than all PDE4s, to produce medicines without side-effects. As all PDE4 enzymes have identical mouths for digesting cAMP we need to take a new approach to inhibit just the critical PDE4s. To do this we will exploit our discovery that individual PDE4s have unique 'postcodes' built into them. These post-codes allow particular PDE4s to be targeted to the right place inside cells for them to work properly. This happens because the individual postcode is recognised by distinct anchor proteins placed at strategically important sites in cells. This targeting to exactly the right place is essential for particular PDE4s to do their job. We aim to identify anchor proteins and relevant postcodes for the PDE4s that we need to inhibit to stop inflammation and lung damage. Then, when we've done this, we will design molecules that stop the postcode of critical PDE4s from being recognised by their anchors. These molecules will prevent PDE4s from going to the place in the cell where they help inflammation to occur. These should provide a new way of making medicines to treat COPD that we anticipate will not suffer side effects caused by medicines currently being developed.

英国呼吸道疾病的死亡率是欧盟平均水平的两倍，NHS的成本高于任何其他疾病领域。慢性阻塞性肺病是世界上第四大死亡原因，在英国每年造成约26，000人死亡，哮喘每年造成约1500人死亡。这种使人衰弱的疾病与慢性炎症引起的肺损伤有关，慢性炎症是由于“炎性”细胞的持续激活。提高这些细胞内一种叫做cAMP的物质的水平，可以阻止这种情况。一种有效的方法是阻止cAMP被PDE 4酶分解。目前，科学家们已经制造出了抑制剂分子，可以紧密结合在PDE 4上的“嘴”上，在那里cAMP被消化，阻止它分解cAMP。然而，使用这些药物的一个主要问题是恶心和呕吐等副作用。现在很清楚，有一个大家族的PDE4酶，其中只有某些在导致肺部炎症和损伤的细胞中发现。我们的目标是确定特定的PDE4酶，它是重要的抑制，以阻止损害和帮助修复肺部。然后，我们需要设计出有选择地抑制这些PDE4的方法，而不是所有的PDE4，以生产没有副作用的药物。由于所有的PDE4酶都有相同的消化cAMP的口，我们需要采取一种新的方法来抑制关键的PDE4。要做到这一点，我们将利用我们的发现，个人PDE4有独特的'邮政编码'内置到他们。这些邮政编码允许特定的PDE4靶向细胞内的正确位置，使它们正常工作。这是因为单个邮政编码被置于细胞中战略性重要位点的不同锚蛋白识别。这种精确定位对于特定的PDE 4完成其工作至关重要。我们的目标是确定锚蛋白和相关的邮政编码的PDE 4，我们需要抑制，以阻止炎症和肺损伤。然后，当我们完成这些工作后，我们将设计分子来阻止关键PDE 4的邮政编码被它们的锚识别。这些分子将阻止PDE4进入细胞中有助于炎症发生的地方。这些应该提供一种新的方法来制造治疗COPD的药物，我们预计这种药物不会受到目前正在开发的药物所引起的副作用。

项目成果

Dimerization of cAMP phosphodiesterase-4 (PDE4) in living cells requires interfaces located in both the UCR1 and catalytic unit domains.

• DOI: 10.1016/j.cellsig.2014.12.009
• 发表时间: 2015-04
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Bolger GB;Dunlop AJ;Meng D;Day JP;Klussmann E;Baillie GS;Adams DR;Houslay MD
• 通讯作者: Houslay MD

Arrestin regulation of small GTPases.

小 GTP 酶的抑制蛋白调节。

• DOI: 10.1007/978-3-642-41199-1_19
• 发表时间: 2014
• 期刊: Handbook of experimental pharmacology
• 作者: Cameron RT

p75 Neurotrophin Receptor Regulates Energy Balance in Obesity.

• DOI: 10.1016/j.celrep.2015.12.028
• 发表时间: 2016-01-12
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Baeza-Raja B;Sachs BD;Li P;Christian F;Vagena E;Davalos D;Le Moan N;Ryu JK;Sikorski SL;Chan JP;Scadeng M;Taylor SS;Houslay MD;Baillie GS;Saltiel AR;Olefsky JM;Akassoglou K
• 通讯作者: Akassoglou K

The activity of cAMP-phosphodiesterase 4D7 (PDE4D7) is regulated by protein kinase A-dependent phosphorylation within its unique N-terminus.

• DOI: 10.1016/j.febslet.2015.02.004
• 发表时间: 2015-03-12
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Byrne AM;Elliott C;Hoffmann R;Baillie GS
• 通讯作者: Baillie GS

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).

• DOI: 10.1016/j.bcp.2013.02.026
• 发表时间: 2013-05-01
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Cameron, Ryan T.;Coleman, Ryan G.;Day, Jon P.;Yalla, Krishna C.;Houslay, Miles D.;Adams, David R.;Shoichet, Brian K.;Baillie, George S.
• 通讯作者: Baillie, George S.