Role of Siah proteins in inflammation and cancer

在这个项目中，我们的目标是确定Siah蛋白在肿瘤血管生成和炎症反应中的作用。低氧是氧分压的降低，限制了肿瘤的生长，而肿瘤通过新的血管形成获得氧气的途径尚未建立。此外，缺氧在炎症和伤口愈合领域很常见，这些领域的血管已经关闭，以帮助恢复。通过使用我们的Siah基因敲除小鼠，我们有了一个独特的模型，这使得我们第一次能够研究Siah在缺氧信号级联中的作用。细胞如何感知和反应低氧水平是复杂的，涉及几种蛋白质。一种关键蛋白质被称为缺氧诱导因子，Hif-1。它在低氧条件下积累，并负责表达使细胞在低氧条件下耐受和发挥功能的基因。在低氧条件下耐受和发挥功能，这与新血管的形成有关。当氧气受限时，PhD蛋白指导HIF1的降解，而Siah则指导PHD的降解。Siah蛋白的丢失(例如，在我们的基因敲除模型中)会导致低氧下PhD蛋白的增加，从而使Hif-1不稳定，并削弱对低氧的反应。因此，坐在控制细胞内蛋白质破坏的级联的顶端(这是今年诺贝尔医学奖的焦点)，Siah对缺氧的反应拥有主要的控制。多细胞生物对获得性缺陷的相对免疫力是通过冗余实现的。氧气是一种独特的情况，对于这种情况，生物体无法通过冗余绕过缺陷，使其成为未来治疗的有吸引力的目标。因此，了解分子和细胞对低氧的反应可能使我们能够确定可能成为新型抗炎和癌症药物开发靶点的关键分子。这项研究的范围是了解Siah利用我们的基因敲除小鼠在炎症和癌症模型中的关键作用。

In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.