Leucine-rich alpha-2-glycoprotein 1 (Lrg1) as a novel modulator of TGFbeta signalling in disease

富含亮氨酸的 α-2-糖蛋白 1 (Lrg1) 作为疾病中 TGFbeta 信号传导的新型调节剂

• 批准号: MR/L002973/1
• 负责人: John Greenwood
• 金额: $ 63.32万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002973%2F1
• 关键词: Leucine; rich; alpha; glycoprotein; Lrg1

Diseases of the vasculature constitute a major burden to human wellbeing and their treatment creates a significant economic cost, particularly in western societies. For example, in the eye proliferative diabetic retinopathy is the leading cause of blindness in the working age population, and the exudative (wet) form of age-related macular degeneration (AMD) is the leading cause of loss of vision in the over 65's. Both diseases are common, highly disabling and increasing in prevalence and are characterised by abnormal blood vessel growth and vessel leakage. In both conditions the molecular mechanisms that lead to pathology are poorly understood and the treatment options are limited. New blood vessel formation also plays a major role in the growth of solid tumours, since a growing mass of cells requires delivery of nutrients and oxygen. Growing tumours promote the formation of new blood vessels in order for them to expand and attempts to destroy or eliminate tumour blood vessels have been the subject of extensive research. To date, however, these approaches have been largely unsuccessful but remain a desirable objective in the pursuit of novel anti-cancer drugs. The blood vessels that form in tumours are also frequently highly disorganised, poorly perfused and leaky, and it is increasingly recognised that if these blood vessels could be 'normalised' this may aid the delivery of therapeutic drugs to the target tumour cells. In our previous work we discovered a protein named Lrg1, that stimulates blood vessel growth and that is required for pathological blood vessel growth in models of eye disease. We also observed that in mice that lack Lrg1, tumours grow much more slowly. We further showed that blocking the activity of Lrg1 using antibodies prevented the formation of abnormal blood vessels in a mouse model of AMD, demonstrating that Lrg1 is a potential therapeutic target in diseases of the vasculature. We have also discovered that Lrg1 modifies the activity of the growth factor TGFbeta and that it is through this interaction that Lrg1 exerts its effect. We found that Lrg1 is frequently expressed by cancer cells, suggesting that this could be one way in which solid tumours stimulate the formation of a blood supply. However, TGFbeta is not only involved in promoting new blood vessel growth but can also make tumour cells more aggressive and prevent the immune system from attacking the tumour. Preliminary experiments have shown that Lrg1 can indeed modulate the activity of TGFbeta in cancer cells and white blood cells and that this may support tumour cell growth and metastasis.In this proposal our objectives are to elucidate the mechanism of how Lrg1 works in cancer cells, blood vessels and cells of the immune system. We already have several important clues from studies performed in our current MRC project grant, in that we know the identity of certain cell surface receptors on blood vessels that interact with Lrg1, and we know some of the consequences of these interactions on cell fate. Here, we will define those interactions in greater detail, to work out not only which receptors Lrg1 binds to on blood vessels, cancer cells and immune cells, but also to define which parts of the Lrg1 molecule are required for those interactions. Using a variety of experimental models of disease, we will examine the consequences of Lrg1 binding to its target cells to determine cellular outcomes. Finally, will use Lrg1 blocking antibodies to find out whether, in these models of disease, therapeutic targeting of Lrg1 diminishes or eliminates the pathology.

脉管系统疾病构成人类健康的主要负担，并且它们的治疗产生显著的经济成本，特别是在西方社会。例如，在眼睛中，增殖性糖尿病视网膜病变是工作年龄人群失明的主要原因，并且渗出性（湿性）形式的年龄相关性黄斑变性（AMD）是65岁以上视力丧失的主要原因。这两种疾病都很常见，致残率很高，患病率也在增加，其特征是血管生长异常和血管渗漏。在这两种情况下，导致病理的分子机制知之甚少，治疗选择有限。新血管的形成在实体瘤的生长中也起着重要作用，因为不断增长的细胞需要输送营养和氧气。生长中的肿瘤促进新血管的形成以使它们扩张，并且破坏或消除肿瘤血管的尝试一直是广泛研究的主题。然而，迄今为止，这些方法在很大程度上是不成功的，但仍然是追求新的抗癌药物的理想目标。在肿瘤中形成的血管也经常高度紊乱，灌注不良和渗漏，并且越来越多地认识到，如果这些血管可以“正常化”，这可能有助于将治疗药物递送到靶肿瘤细胞。在我们之前的工作中，我们发现了一种名为Lrg 1的蛋白质，它刺激血管生长，并且是眼病模型中病理性血管生长所必需的。我们还观察到，在缺乏Lrg1的小鼠中，肿瘤生长得更慢。我们进一步表明，使用抗体阻断Lrg1的活性可以防止AMD小鼠模型中异常血管的形成，表明Lrg1是血管疾病的潜在治疗靶点。我们还发现，Lrg1改变了生长因子TGF β的活性，正是通过这种相互作用，Lrg1发挥了作用。我们发现Lrg1经常被癌细胞表达，这表明这可能是实体瘤刺激血液供应形成的一种方式。然而，TGF β不仅参与促进新血管生长，还可以使肿瘤细胞更具攻击性并阻止免疫系统攻击肿瘤。初步的实验表明，Lrg 1确实可以调节肿瘤细胞和白色血细胞中TGF β的活性，这可能有助于肿瘤细胞的生长和转移。本研究的目的是阐明Lrg 1在肿瘤细胞、血管和免疫系统细胞中的作用机制。我们已经从我们目前的MRC项目资助中进行的研究中获得了几个重要的线索，因为我们知道血管上与Lrg1相互作用的某些细胞表面受体的身份，并且我们知道这些相互作用对细胞命运的一些后果。在这里，我们将更详细地定义这些相互作用，不仅要确定Lrg1与血管、癌细胞和免疫细胞上的哪些受体结合，还要确定Lrg1分子的哪些部分是这些相互作用所必需的。使用各种疾病的实验模型，我们将研究Lrg1结合其靶细胞的后果，以确定细胞结果。最后，将使用Lrg1阻断抗体来确定在这些疾病模型中，Lrg1的治疗靶向是否减少或消除了病理。

项目成果

LRG1 as a novel therapeutic target in eye disease.

• DOI: 10.1038/s41433-021-01807-4
• 发表时间: 2022-03
• 期刊: Eye (London, England)
• 作者: De Rossi G;Da Vitoria Lobo ME;Greenwood J;Moss SE
• 通讯作者: Moss SE