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Understanding TGF beta activation in health and disease

了解健康和疾病中的 TGF β 激活

基本信息

批准号：
MR/M009831/1
负责人：
Penny Handford
金额：
$ 53.23万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FM009831%2F1
关键词：
Understanding TGF beta activation health

项目摘要

The TGF ( transforming growth factor) beta signalling pathway plays an essential role in many aspects of biology, including development of the embryo and maintenance of adult tissues. There are three different forms of TGF beta, each of which is secreted from cells in the form of an inactive or latent complex, and this complex is itself often bound to a much larger protein called latent transforming growth factor beta binding protein (LTBP). This large protein ensures that TGF beta is sequestered in the extracellular matrix, an insoluble collection of proteins and carbohydrates which surround cells, where it can be activated in response to specific signals and delivered to its receptor in a carefully regulated manner. Subsequent binding of TGFbeta to its receptor leads to many different cellular effects in tissues. This signalling pathway is disrupted in many different genetic and acquired diseases, such as cancer, autoimmune and inflammatory disorders and heritable diseases of the connective tissues including Marfan syndrome. We have recently identified one of the ways in which LTBP is localised to the extracellular matrix, by its interaction with a protein called fibrillin-1. We believe that studying this interaction in detail will provide insight into how TGF beta is released in an active form from the matrix, and how various diseases associated with excessive levels of TGF beta activation arise. Furthermore this basic science may provide new ways of designing drugs such as monoclonal antibodies or small molecule activators or inhibitors which will be invaluable in a research or clinical setting to manipulate the TGF beta signal.

TGF（转化生长因子）β信号通路在生物学的许多方面起着至关重要的作用，包括胚胎的发育和成年组织的维持。有三种不同形式的TGF β，每种形式都以无活性或潜在复合物的形式从细胞中分泌，并且这种复合物本身通常与一种更大的蛋白质结合，称为潜在转化生长因子β结合蛋白（LTBP）。这种大蛋白质确保TGF β被隔离在细胞外基质中，细胞外基质是细胞周围蛋白质和碳水化合物的不溶性集合，在那里它可以响应特定信号而被激活，并以仔细调节的方式递送到其受体。随后TGF β与其受体的结合导致组织中许多不同的细胞效应。这种信号通路在许多不同的遗传和获得性疾病中被破坏，例如癌症、自身免疫性和炎性疾病以及结缔组织的遗传性疾病，包括马凡氏综合征。我们最近已经确定了LTBP定位于细胞外基质的方式之一，通过其与一种称为蛋白质的相互作用。我们相信，详细研究这种相互作用将有助于深入了解TGF β是如何以活性形式从基质中释放出来的，以及与TGF β过度活化相关的各种疾病是如何产生的。此外，这一基础科学可以提供设计药物的新方法，如单克隆抗体或小分子活化剂或抑制剂，这在研究或临床环境中将是非常宝贵的，以操纵TGF β信号。