The Role of Angiopoietins 1 and 2 in ANCA Associated Vasculitis

血管炎包括一组以炎症和血管破坏为特征的疾病。抗中性粒细胞胞浆抗体(ANCA)血管炎是一种血管炎的亚型，其中白细胞被血液中通常抗感染的蛋白质激活。然后这些白血球攻击全身血管，包括肾脏。未经治疗的脉管炎预后非常差，许多患者的肾脏严重受损，因此需要透析。目前，治疗血管炎的主要方法是对免疫系统进行实质性的抑制，这本身就与显著的发病率和死亡率有关。在细胞水平上更好和更清楚地了解血管炎的发病机制将有助于改进治疗方法。我们的目标是探索称为血管生成素1和2的生长因子的作用。内皮(血管内细胞表面)被认为驱动炎症，最终导致其自身破坏，并导致与血管炎相关的并发症。血管生成素在维持内皮完整性方面起着重要作用，我们预测它们在与血管炎相关的炎症循环中起着至关重要的作用。了解血管内皮细胞和免疫系统的相互作用将有助于发现更有针对性的治疗方案，并改善血管炎的预后。血管生成素1和2由不同的血管成分组成。血管生成素在器官发育和肿瘤生物学中的作用已经被探索，但它在血管炎中的活动性血管炎症中的作用还没有被探索。已公布的数据显示，这些生长因子确实会影响免疫系统的细胞，使它们与炎症有关。由于基因干预而不产生血管生成素2的小鼠对通常由细菌诱导的炎症具有抵抗力。血管生成素-1在实验室中已被证明对分离的血管具有抗炎作用。先前的工作和我们自己的初步数据表明，活动期血管炎患者的血液样本中血管生成素-2的水平显著高于对照组。此外，我们有新的数据表明，血管生成素2影响一类参与血管炎发病的特定类型的白细胞。了解血管生成素的作用并将其作为靶点，将有助于通过减少血管疤痕来改变疾病的预后，并有望导致更有针对性的治疗，这是迫切需要的。我们将在这个项目中解决的重要问题包括：-血管如何通过产生血管生成素来操纵血管炎中的炎症？-血管生成素如何影响肾血管细胞本身？-血管生成素如何参与对血管炎至关重要的白细胞的招募，以及它们如何改变白细胞的行为？-血管生成素如何影响啮齿动物模型血管炎的炎症程度？-当我们在啮齿动物模型的血管炎中阻断血管生成素2的作用时会发生什么？这可能是一种对患者有用的治疗方法？

Vasculitis encompasses a group of disorders characterised by inflammation and destruction of blood vessels. Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is a subtype of vasculitis in which white blood cells are activated by proteins in the blood that normally fight infection. These white blood cells then attack blood vessels throughout the body including the kidneys. The outcome of untreated vasculitis is very poor and in many patients the kidneys are severely damaged so that dialysis is needed. At present the mainstay of treatment in vasculitis is substantial suppression of the immune system, which in itself is associated with significant morbidity and mortality. A better and clearer understanding of the mechanisms that underlie the cause of vasculitis at a cellular level will help refine therapy.Our objective is to explore the role of growth factors called angiopoietins 1 and 2. The endothelium (internal cell surface of blood vessels) is thought to drive the inflammation which ultimately leads to its own destruction and leads to the complications associated with vasculitis. Angiopoietins have a role in the maintenance of the endothelium integrity and we predict that they have a crucial role in the inflammatory cycle associated with vasculitis. An understanding of the endothelium and immune system interaction will help in the discovery of more focused treatment options and improve the prognosis of vasculitis.Angiopoietins 1 and 2 are made by different blood vessel constituents. The role of angiopoietins have been explored in development of organs and in tumour biology, however its role in active blood vessel inflammation in vasculitis has not been explored. Published data show that these growth factors do influence the cells of the immune system, implicating them in inflammation. Mice that do not make angiopoietin 2 due to genetic interventions are resistant to inflammation that would normally be induced by bacteria. Angiopoietin 1 has been shown to have anti inflammatory effects on isolated blood vessels in the laboratory.Previous work and our own preliminary data show that angiopoietin 2 levels are significantly higher in blood samples from patients with active vasculitis in comparison to control subjects. Furthermore we have novel data which shows that angiopoietin 2 affects a specific class of white cells involved in vascultis pathogenesis. Understanding the role of angiopoietins and targeting them will help alter the prognosis of the disease by causing less scarring of blood vessels and will hopefully lead to more targeted therapy which is much needed. Important questions we will address in this project include:- How do the blood vessels manipulate the inflammation in vasculitis by the production of angiopoietins?- How do angiopoietins impact on the kidney blood vessel cells themselves?- How are angiopoietins involved in recruitment of white blood cells crucial in vasculitis and how do they change the behaviour of the white blood cells?- How do angiopoietins affect the degree of inflammation in a rodent model of vasculitis?- What happens when we block the effect of angiopoietin 2 in a rodent model of vasculitis and may this be a useful treatment in patients ?