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

在生命早期，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，它能有效地提高神经细胞（神经元）的存活率。同样，这个系统对脑损伤（如中风）的反应是活跃的，但它也可能提高肿瘤的存活率。在所有这些过程中，调节igf对神经元的可用性是至关重要的。IGF结合蛋白-2 （IGFBP-2）在发育或受损的大脑和肿瘤中含量丰富，在神经元表面调节IGF的可用性中起关键作用。我们已经证明，IGFBP-2与神经细胞上的一种特殊蛋白质相关联，在那里它被进一步加工成更小的片段。我们认为这些过程在脑损伤后或在IGFBP-2高度丰富的癌症状态下被重新激活。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个步骤的功能。我们将通过检测IGFBP-2突变版本的影响来实现这一目标，该突变版本旨在阻止其与细胞表面的结合或将其加工成更小的片段。我们将使用各种人类和小鼠神经细胞进行这些研究，这不仅将提供对发育中的脑细胞中IGF可用性的调节的更好理解，而且还指出这些过程如何参与增强损伤或中风的恢复，或可能加速肿瘤生长。这项研究的发现将为改变IGF系统的功能提供新的、令人兴奋的治疗方法，使其在脑损伤或中风时更活跃，或在脑肿瘤中更不活跃。

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.