IGF BINDING PROTEIN-2 A MODULATOR OF IGF ACTION IN DEVELOPING AND NEOPLASTIC NEURONAL CELLS.

在生命的早期，大脑经历了快速的生长和重塑，这一过程受到许多因素的调节，包括胰岛素样生长因子(IGF)系统，它有效地提高了神经细胞(神经元)的存活。同样，这种系统在应对中风等脑损伤时是活跃的，但它也可能提高肿瘤的存活率。在所有这些过程中，调节IGFS对神经元的可用性是至关重要的。胰岛素样生长因子结合蛋白-2(IGFBP-2)在发育中或受损的脑以及肿瘤中含量非常丰富，在调节IGF的可获得性方面在神经元表面起着关键作用。我们已经证明IGFBP-2与神经细胞上的一种特殊蛋白质有关，在那里它被进一步加工成更小的片段。我们认为，在脑损伤后或在IGFBP-2高度丰富的癌症状态下，这些过程会重新激活。我们建议确定IGFBP-2如何影响IGF在神经细胞表面的作用，并进一步确定这一过程中每一步的功能。我们将通过检查IGFBP-2突变版本的影响来实现这一点，该突变版本旨在防止其与细胞表面结合或阻止其处理更小的片段。我们将使用不同的人类和小鼠神经细胞进行这些研究，这不仅将提供更多的了解IGF对发育中的脑细胞的可获得性的调节，还将指出这些过程可能如何参与促进损伤或中风的恢复，或者可能参与加速肿瘤的生长。这项研究的发现将提供新的令人兴奋的治疗方法的可能性，旨在改变IGF系统的功能，使其在应对脑损伤或中风时更活跃，或在脑瘤中不那么活跃。

In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged brain, and in tumours, plays a key role on the surface of neurons in regulating IGF availability. We have shown that IGFBP-2 associates with a specialised protein on the nerve cells, where it is further processed to smaller fragments. We believe that these processes are reactivated following brain injury or in cancer states where IGFBP-2 is highly abundant. We propose to determine how IGFBP-2 influences IGF action on the nerve cell surface, and to further ascertain the function of each step in this process. We will achieve this by examining the effects of the mutated version of IGFBP-2, designed to either prevent its binding to the cell surface or its processing to smaller fragments. We will use various human and mouse nerve cell for these studies, which will not only provide greater understanding of the regulation of IGF availability to developing brain cell, but also point to how these processes may be involved in enhancement of recovery from injury or stroke, or possibly in acceleration of tumour growth. The finding of this study will offer the potential for new and exciting treatment designed to alter the function of the IGF system, to either make it more active in response to brain injury or stroke, or less active in brain tumours.