Regulation of VEGF splicing

VEGF 剪接的调节

• 批准号: BB/J007293/1
• 负责人: David Bates
• 金额: $ 60.32万
• 依托单位: University of Bristol
• 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=BB%2FJ007293%2F1
• 关键词: Regulation; VEGF; splicing

Vascular Endothelial Growth Factor is fundamental regulator of blood vessel growth (angiogenesis). It is responsible for blood vessel growth in all tissues in human development from the embryo to the newborn child. It is also key to growth of tissues as children develop into adults, and in adults it is necessary in normal physiology during tissue remodelling (e..g in muscle growth in response to exercise) and in many diseases including cancer, diabetes and heart disease . Over the last three years, our research group has discovered that the way that cells edit together the message encoded by the gene that codes for the most important growth factor for blood vessels (called VEGF) results in two different families of proteins called VEGFxxx and VEGFxxxb. The VEGFxxxb family is widely expressed in normal human tissues, but switched off during angiogenesis, when the VEGFxxx family take over. The VEGFxxx family stimulates blood vessel growth, whereas the VEGFxxxb stops vessels growing, and we have recently identified many new functions of this family - they protects cells from injury, stop development of pain, maintain kidney function, and control fertility. It is now clear that this alternative editing (splicing) is controlled by cells, and appears to switch during angiogenesis and other cell stresses. However, little is known about how cells balance expression of the two families of isoforms by regulating splicing of VEGF in normal tissues. This area is beyond the scope of the medical research charities currently supporting our work to find out whether these isoforms can be used to treat cancers, heart disease, diabetes, pain, renal failure and other conditions. This project aims to determine the molecular and cellular pathways that regulate the balance of splicing of the VEGF mRNA. It will identify some of the molecules that control these splicing events, determine the sequences within the VEGF gene that are recognised by splicing factors, and identify how and where this splicing balance alters in live animals. It will do so using a new, cutting edge technology of in vivo splice reporters. These are synthetic DNA sequences that code for green or red proteins depending on which forms are made. These sequences can be used to follow in real time in live cells which way splicing is happening. This is the only way that splicing can be followed within a live single cell in response to treatments, to normal function, or growth or changes in animals. These new sequences are unique to the laboratory in Bristol, and we wish to exploit this advantage over competing groups in the USA to generate advances in scientific understanding from a UK base.

血管内皮生长因子是血管生长（血管生成）的基本调节因子。它负责从胚胎到新生儿的人类发育中所有组织的血管生长。它也是儿童发育成成人时组织生长的关键，并且在成人中，在组织重塑期间（例如，在正常生理学中），它是必要的。例如，肌肉对运动的反应）以及许多疾病，包括癌症、糖尿病和心脏病。在过去的三年里，我们的研究小组发现，细胞编辑由编码血管最重要的生长因子（称为VEGF）的基因编码的信息的方式导致两种不同的蛋白质家族，称为VEGFxxx和VEGFxxxb。VEGFxxxb家族在正常人体组织中广泛表达，但当VEGFxxx家族接管时，在血管生成过程中关闭。VEGFxxx家族刺激血管生长，而VEGFxxxb阻止血管生长，我们最近发现了这个家族的许多新功能-它们保护细胞免受损伤，阻止疼痛的发展，维持肾功能和控制生育。现在很清楚的是，这种选择性编辑（剪接）是由细胞控制的，并且似乎在血管生成和其他细胞应激期间发生变化。然而，关于细胞如何通过调节正常组织中VEGF的剪接来平衡两个亚型家族的表达，知之甚少。这一领域超出了目前支持我们工作的医学研究慈善机构的范围，这些慈善机构正在研究这些异构体是否可以用于治疗癌症，心脏病，糖尿病，疼痛，肾衰竭和其他疾病。该项目旨在确定调节VEGF mRNA剪接平衡的分子和细胞途径。它将确定一些控制这些剪接事件的分子，确定剪接因子识别的VEGF基因内的序列，并确定这种剪接平衡在活体动物中如何以及在何处改变。它将使用一种新的、尖端的体内剪接报告技术来实现这一点。这些是合成的DNA序列，编码绿色或红色蛋白质，这取决于形成的形式。这些序列可以用于在活细胞中以真实的时间跟踪剪接发生的方式。这是唯一的方式，剪接可以在一个活的单细胞内响应治疗，正常功能，或生长或动物的变化。这些新的序列是布里斯托实验室所独有的，我们希望利用这一优势，在美国的竞争群体中产生来自英国基地的科学理解的进步。

项目成果

Circulating levels of anti-angiogenic VEGF-A isoform (VEGF-Axxxb) in colorectal cancer patients predicts tumour VEGF-A ratios.

结直肠癌患者中抗血管生成 VEGF-A 异构体 (VEGF-Axxxb) 的循环水平可预测肿瘤 VEGF-A 比率。

• 发表时间: 2015
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Bunni J

Pharmacology of Modulators of Alternative Splicing.

• DOI: 10.1124/pr.115.011239
• 发表时间: 2017-01
• 期刊: Pharmacological reviews
• 影响因子: 21.1
• 作者: Bates DO;Morris JC;Oltean S;Donaldson LF
• 通讯作者: Donaldson LF

The many faces of SRPK1.

• DOI: 10.1002/path.4846
• 发表时间: 2017-03
• 期刊: The Journal of pathology
• 作者: Bullock N;Oltean S
• 通讯作者: Oltean S

Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion.

• DOI: 10.1136/jclinpath-2015-203125
• 发表时间: 2016-02
• 期刊: Journal of clinical pathology
• 影响因子: 3.4
• 作者: Bullock N;Potts J;Simpkin AJ;Koupparis A;Harper SJ;Oxley J;Oltean S
• 通讯作者: Oltean S

Detection of VEGF-A(xxx)b isoforms in human tissues.

在人体组织中检测VEGF-A（XXX）B同工型。

• DOI: 10.1371/journal.pone.0068399
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bates DO;Mavrou A;Qiu Y;Carter JG;Hamdollah-Zadeh M;Barratt S;Gammons MV;Millar AB;Salmon AH;Oltean S;Harper SJ
• 通讯作者: Harper SJ