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

这项研究结合了分子科学，细胞生物学和疾病过程-它是在分子医学。该研究计划的重点是人胰岛素和胰岛素样生长因子I和II（IGF-I/II）;这些都是密切相关的蛋白质激素。它们的独立进化导致它们获得独立的生物学功能，胰岛素成为代谢的关键调节因子，而IGF-I/II是主要的生长因子。当释放到血液中时，激素紧密且特异性地结合到它们的受体（分别为胰岛素受体（IR）和IGF-1 R）;这些是细胞表面上的大的复杂蛋白质分子。通过受体结合来表达激素活性，涉及激素和受体的结构变化。尽管它们具有基本的医学重要性（胰岛素：在糖尿病中，IGFs：在发育，癌症，衰老中），但激素在其激素：受体复合物中的活性构象尚不清楚。因此，在第一个胰岛素晶体结构被确定40多年后，用于治疗糖尿病的所有类似物仍然基于这种激素的非活性/储存形式。胰岛素与IGF-1 R的交叉反应及其在2型糖尿病中的积累使得这种激素参与细胞增殖和生长。由于IGF-I/II也是癌症特异性生长因子，因此胰岛素和IGF-I/II的纯“代谢”和“细胞生长”结构特征的鉴定不仅对于理解这些激素的生物学，而且对于糖尿病和癌症的新的有效治疗具有根本重要性。因此，该计划是对迫切需要对胰岛素和IGF-I/II结构和生物学的这些关键问题进行独特的，统一的和多学科的攻击的回应。该计划结合了基础（结构生物学，细胞信号传导，有机和蛋白质化学）和应用研究。基础研究为该计划奠定了基础。然而，该小组在应用生物医学科学方面的先进专门知识也将使人们能够同时追求应用目标。该方案将提供：（i）胰岛素：IR复合物的三维结构描述;阐明人胰岛素的活性形式，（ii）鉴定胰岛素中负责代谢作用的活性表面，（iii）开发新的、特异性代谢胰岛素类似物，（iv）鉴定胰岛素样生长因子-I/II的促有丝分裂结构特征我们相信，对分子细胞生物学和医学科学的潜在影响是巨大的，因为它直接解决了两个主要的健康问题，糖尿病和癌症。两者都产生了巨大的社会和经济后果。(i)首先，解决糖尿病的核心问题：胰岛素-胰岛素受体（IR）相互作用，即胰岛素从其储存形式活化为IR刺激构象，将为理解胰岛素结构-功能关系提供期待已久的突破，并为合理设计新型胰岛素开辟新的可能性。(ii)随后，确定胰岛素和IGF-I/II的结构决定因素，这些结构决定因素支配其特定的信号传导途径，并负责这些激素的代谢和生长特异性，这将增强合理设计和生产纯和安全胰岛素的前景，而不具有不期望的促有丝分裂特性。这是一些目前使用的临床类似物所指出的问题。(iii)这些研究应该允许启动IGF-I/II特异性拮抗剂的合理设计和合成，用于新型抗癌治疗。(iv)该方案中对激素化学的严格控制也将允许开始合理设计和合成胰岛素的有机模拟物，这可能导致适合口服的胰岛素样药物。

This research combines molecular science, cell biology and disease processes - it is in molecular medicine. The research programme focuses on human insulin and Insulin-like Growth Factors I and II (IGF-I/II); these are closely related protein hormones. Their separate evolution has resulted in their acquiring separate biological functions, with insulin becoming a key regulator of metabolism, while IGF-I/II are major growth factors. When released into the blood the hormones bind, tightly and specifically, to their receptors, (Insulin Receptor (IR) and IGF-1R respectively); these are large complex protein molecules on the cell surface. Receptor binding, through which the hormone activity is expressed, involves structural changes in both the hormone and the receptors. Despite their fundamental medical importance (insulin: in diabetes, IGFs: in development, cancer, aging) the active conformations of the hormones in their hormone:receptor complexes are not known. Thus, more than 40 years after the first insulin crystal structure was determined, all the analogues used in treatment of diabetes are still based on the inactive/storage forms of this hormone. Insulin cross-reation with IGF-1R and its accumulation in Type 2 Diabetes entails this hormone in cell proliferation and growth. As IGF-I/II are also cancer-specific growth factors the identification of pure 'metabolic' and 'cell growth' structural signatures of insulin and IGF-I/II is of fundamental importance not only for the understanding of the biology of these hormones, but also for new, effective treatments of diabetes and cancer. Therefore this Programme is a response to an urgent need for a unique, consolidated, and multidisciplinary attack on these critical problems of insulin and IGF-I/II structure and biology. This programme combines fundamental (structural biology, cell signaling, organic and protein chemistry) and applied research. The fundamental research provides the foundations of the programme. However, advanced expertise of this group in the applied biomedical sciences will enable parallel pursuit of applied aims as well. This programme will deliver: (i) 3-D structural description of insulin:IR complexes; elucidation of the active form of human insulin, (ii) identification of active surfaces in insulin's responsible for metabolic effects, (iii) development of novel, specific metabolic insulin analogues, (iv) identification of the mitogenic structural signatures of the Insulin-like Growth Factors-I/II (IGF-I/II) expressed through IR, (vi) initiation of developing organo/peptido-mimetics of these hormones.We believe that the potential impacts on molecular cell biology and on medical science are immense as it addresses directly two major health problems, diabetes and cancer. Both have enormous social and economic consequences. (i) Firstly, solution of the central problem of diabetes: insulin-Insulin Receptor (IR) interaction, i.e. activation of insulin from its storage form to its IR stimulating conformation, will provide a long-awaited breakthrough in understanding of insulin structure-function relationships and open new possibilities for rational design of novel insulins. (ii) Subsequently, identification of structural determinants of insulin and IGF-I/II that govern their specific signaling pathways and which are responsible for metabolic and growth specificity of these hormones should enhance the prospects for rational design and production of pure and safe insulins without their undesired mitogenic properties. This is a problem indicated by some currently used clinical analogues. (iii) The studies should allow initiation of rational design and synthesis of IGF-I/II-specific antagonists for novel anti-cancer therapies. (iv) The firm control on hormone chemistry within this programme will also allow initiation of rational design and synthesis of organo-mimics of insulin, which may lead to insulin-like drugs suitable for oral delivery.