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

点击翻译按钮获取中文摘要

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.