Elucidation of the role of the molecular chaperone AIP in familial acromegaly

最近，AIP(芳烃受体相互作用蛋白)基因的异常变化(突变)被证明导致生长激素过量的家族性垂体肿瘤，导致异常身高(巨人症)或手、脚和其他器官增大(肢端肥大症)。这个项目将研究AIP的功能以及AIP基因突变导致肢端肥大症的确切方式。该项目将研究正常和突变的AIP蛋白在细胞系和组织中的特征和功能。我们将使正常和异常AIP水平升高的细胞。我们还将降低细胞内的AIP水平。在这两种情况下，我们都会将这些特征与正常细胞进行比较。我们将进一步描述我们的家族性肢端肥大症患者的临床特征和肿瘤类型，这是世界上最大的集合之一。我们相信，探索该基因在这种相对罕见的家族性疾病中是如何发挥作用的，将使我们能够了解垂体细胞的生理学和病理生理学，可能更常见的散发性垂体腺瘤。因此，该项目将在实验室科学和临床研究方面提供平衡的培训，使申请人能够学习基本技能，这对他在学术医学领域工作的长期目标将是有价值的。

Recently abnormal changes (mutations) in the AIP (aryl-hydrocarbon receptor-interacting protein) gene have been shown to result in familial pituitary tumours with excess growth hormone causing abnormally tall stature (gigantism) or enlargement of the hands, feet and other organs(acromegaly). This project will investigate the function of AIP and the exact way by which mutations in the AIP gene results in acromegaly. The project will study the characteristics and function of normal and mutated AIP protein in cell lines and tissues. We will make cells with elevated levels of both normal and abnormal AIP. We will also reduce AIP levels in cells. In both instances we will compare the characteristics to normal cells. We will further characterise our familial acromegaly patients, one of the largest collections in the world, in terms of clinical features and the type of tumour they have. We believe that exploring how this gene works in this relatively rare familial disease will allow us to understand the physiology and pathophysiology of pituitary cells and possibly the more common sporadic pituitary adenomas. This project therefore will provide a balanced training both in laboratory science and in clinical research, allowing the applicant to learn essential skills, which will be valuable for his long-term goal of working in academic medicine.