MICA: A molecular dissection of the interplay between diabetes and cancer: an integrated, multidisciplinary approach. II.

该研究计划的重点是人胰岛素和胰岛素样生长因子-1和2（IGF 1/2）的详细作用;这些都是密切相关的蛋白质激素。通过进化，它们获得了不同的生物学功能，胰岛素成为代谢的关键调节因子，而IGF 1/2是细胞生长和分化背后的主要生长因子。这些激素的活性水平决定了我们在生活方式，饮食和疾病面前生活的时间和健康程度。当释放到血液中时，激素紧密而特异地结合到它们的受体：胰岛素（IR）和IGF-1 R，分别是细胞表面的大的复杂蛋白质分子。受体结合，通过其激素活性被传递到细胞中，涉及激素和受体的结构变化。在这里，我们的目标是了解激素信号从细胞外到细胞内的翻译中的关键事件。 尽管它们具有基本的医学重要性，例如1型糖尿病（T1 D）和2型糖尿病（T2 D）中的胰岛素信号传导功能障碍，但IGF 1/2是癌症的主要驱动因素，目前仍不清楚这些激素如何通过其受体实现其特定信号并诱导不同的生物学效应。胰岛素和IG 1/2分子作用的复杂性由于存在两种非常相似的IR形式以及这些激素以某种方式结合所有受体的能力而进一步复杂化。有两种形式的IR; IR-B形式控制胰岛素的代谢作用，而IR-A也结合IGF 1/IGF 2，并可刺激细胞生长和增殖。 胰岛素和IGF 1/2的这种非常复杂且相互交织的分子活性是其巨大的社会和人类健康影响的基础。NHS预算中约有2500万英镑/天用于T2 D，主要用于治疗相关并发症，如心血管和肾脏疾病，癌症和神经退行性疾病。因此，迫切需要了解胰岛素和IGF 1/IGF 2在激素和受体水平的特异性。这可以用于设计和递送新的，更安全的胰岛素（类似物）形式，以及具有抗癌和有益（例如抗神经退行性）选择性特性的新IGF 1/2类似物，而没有糖尿病中观察到的副作用。该研究计划通过提供综合的多学科（结构，化学和细胞生物学）方法来应对这一挑战，解决胰岛素和IGF 1/2生物学的所有关键方面：激素，受体和细胞。基础研究是该计划的基石。然而，该小组在应用生物医学科学方面的先进专业知识将使彻底的临床翻译为不同条件的患者带来好处。该方案将提供：- 在受体水平上：（i）胰岛素与其受体IR-A和IR-B结合的描述，（ii）IR-A和IR-B细胞外胰岛素结合部分的结构特征的描绘，（iii）胰岛素触发的信号如何在IR和IGF-1 R受体中转导到细胞内部，（iv）胰岛素和IGF 1/2通过其受体特异性作用的结构决定因素是什么-在激素水平上：（i）描述人胰岛素的代谢和促有丝分裂元件，（ii）描述其特异性背后的IGF 1/IGF 2激素决定簇，（iii）开发高代谢、安全的胰岛素类似物，（iv）开发IGF-1 R特异性IGF 1和IGF 2类似物，包括在细胞水平上具有抗癌适用性的IGF-1 R拮抗剂：（i）描述IR-A、IR-B和IGF-1 R对人肌肉和脂肪组织中胰岛素激活的葡萄糖摄取的贡献，（ii）开发具有特异性受体的高级人细胞系统以优化胰岛素类似物的开发，以及用于T2 D的研究，（iii）验证葡萄糖转运研究中使用的现有人体组织模型。

This research programme focuses on the detailed actions of human insulin and Insulin-like Growth Factors-1 and 2 (IGF1/2); these are closely related protein hormones. Through evolution they acquired separate biological functions, with insulin becoming a key regulator of metabolism, while IGF1/2 are major growth factors behind cell growth and differentiation. The levels of activity of these hormones determine how long and how healthy we live in the face of lifestyle, diet and disease. When released into the blood the hormones bind, tightly and specifically, to their receptors: Insulin- (IR) and IGF-1R, respectively, large complex protein molecules on the cell surface. Receptor binding, through which the hormone activity is delivered into cells, involves structural changes in both the hormone and the receptors. Here we aim to understand the key events in the translation of hormone signal from the outside to the inside of the cell. Despite their fundamental medical importance, such as insulin signaling malfunctions in Type 1 (T1D) and Type 2 Diabetes (T2D), IGF1/2 are major drivers of cancer, it is still not understood how these hormones achieve their specific signals and induce different biological effects via their receptors. The complexity of insulin & IG1/2 molecular actions are further convoluted by the existence of two, very similar forms of the IR, and the ability of these hormones to bind in some way to all receptors. There are two forms of the IR; the IR-B form controls metabolic actions of insulin, while IR-A binds also IGF1/IGF2, and can stimulate cell growth and proliferation. This very complex, and intertwined molecular activity of insulin and IGF1/2 is the basis of their huge societal and human health impact. ~£25mln/day of the NHS budget is spent on T2D, largely to treat associated complications such as cardiovascular and kidney disorders, cancer, and neurodegeneration. Hence there is an urgent need to understand insulin and IGF1/IGF2 specificity at the hormonal and receptor level. This could be then exploited in the design and delivery of new, safer, forms of insulin (analogues), and new IGF1/2 analogues with anti-cancer and beneficial (e.g. anti-neurodegenerative) selective properties, without side-effects seen in diabetes. This research programme is responding to this challenge by offering a consolidated, multidisciplinary (structural, chemical and cell biology) approach to these problems, addressing all the key aspect of insulin & IGF1/2 biology: hormones, receptors and cells.Fundamental research is the foundation cornerstone of this programme. However, the advanced expertise of this group in applied biomedical sciences will enable thorough clinical translation for the benefit of patients with different conditions. This programme will deliver: - on the receptor level: (i) the description of insulin binding to its receptors IR-A and IR-B, (ii) delineation of the structural signatures in the IR-A and IR-B extracellular, hormone-binding parts, (iii) how the hormone-triggered signal is transduced to the inside of the cell in IR and IGF-1R receptors, (iv) what are the structural determinants of insulin and IGF1/2 specific actions through their receptors- on the hormone level: (i) description of the metabolic and mitogenic elements of human insulin, (ii) description of IGF1/IGF2 hormonal determinants behind their specificities, (iii) development of highly-metabolic, safe insulin analogues, (iv) development of IGF-1R specific IGF1 and IGF2 analogues, including IGF-1R antagonist with anti-cancer applicability-on the cell-level: (i) description of the contribution of IR-A, IR-B and IGF-1R to hormone-activated glucose uptake into human muscle and fat tissue, (ii) development of advanced human cell-systems with specific receptors to optimise development of insulin analogues, and for study of T2D, (iii) validation of the available human tissue models used in glucose transport studies.