Role of SRPK1 in peripheral ischemia

SRPK1 在外周缺血中的作用

• 批准号: 2270210
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2270210
• 关键词: Role; SRPK1; peripheral; ischemia

Atherosclerosis causes ischemia, stimulating extravasation/differentiation of monocytes into macro-phages, which secrete factors, including VEGF, that induce collateral vessel formation. This collat-eralisation is impaired in patients with peripheral vascular disease (PVD), where circulating mono-cytes express the anti-angiogenic splice variant, VEGF-A165b. In mouse models of PVD and obesity, this variant is upregulated. Neutralisation of VEGF-A165b allows regrowth of collaterals, and restores blood flow in these models, suggesting that prevention of VEGF-A165b expression could be therapeu-tically useful in diabetic PVD. We now have evidence that stimulation of splicing factor kinases that phosphorylate Serine-Arginine rich (SR) proteins controlling alternative splicing are critical regulators of collateral formation in peripheral ischemia, through their action in monocytes. We have shown in mice that inhibition of the splicing factor kinase SRPK1, pharmacologically, or by monocyte specific knockout, can prevent impaired collateral formation and restore blood flow in transgenic animals with hyperactivated monocyte Wnt5a signalling. We now intend to determine a) whether this mechanism is effective in type II diabetes. b) the mechanisms through which SRPK1 inhibition or knockout in monocytes result in enhanced collateral growth.

动脉粥样硬化引起缺血，刺激单核细胞外渗/分化成巨噬细胞，巨噬细胞分泌诱导侧支血管形成的因子，包括VEGF。这种协同作用在外周血管疾病（PVD）患者中受损，其中循环单细胞表达抗血管生成剪接变体VEGF-A165 b。在PVD和肥胖的小鼠模型中，该变体被上调。在这些模型中，VEGF-A165 b的中和允许侧枝再生，并恢复血流，这表明预防VEGF-A165 b表达可能对糖尿病PVD有治疗作用。我们现在有证据表明，刺激剪接因子激酶，磷酸化丝氨酸-精氨酸丰富（SR）的蛋白质控制选择性剪接是在外周缺血侧支形成的关键调节剂，通过其在单核细胞中的作用。我们已经在小鼠中表明，剪接因子激酶SRPK 1，SRPK 2的抑制，或通过单核细胞特异性敲除，可以防止受损的侧支形成，并恢复具有过度活化的单核细胞Wnt 5a信号转导的转基因动物的血流。我们现在打算确定a）这种机制是否对II型糖尿病有效。B）单核细胞中SRPK 1抑制或敲除导致侧枝生长增强的机制。