The pharmacological relevance of pro-peptide of GDNF family members

布景主题：健康生物科学2型糖尿病和代谢疾病更普遍地与心血管疾病一起影响越来越多的人。人们对胰腺β细胞和心肌细胞的再生方法很感兴趣。TGF β家族蛋白质在细胞发育和分化以及疾病中起重要作用，并且BMP 2已被成功开发并作为骨生长的再生因子销售。生长因子的GDNF亚家族通常用作神经营养因子，但特别是neurturin已显示对糖尿病动物具有有益作用，以胰岛素依赖性方式降低其葡萄糖水平。虽然其机制尚不清楚，但neurturin作为治疗剂的使用受到其不良药效学特性和有限组织分布的影响。neurturin和所有GDNF样蛋白一样，是作为更大的前体合成的。我们最近展示了激活素A与其前肽复合时如何具有非常不同的性质。我们假设neurturin的前体形式与迄今为止用于评估治疗潜力的成熟蛋白质类似地不同。该项目的目的是生产neurturin的前体形式，并分析其生化、生物和结构活性。同时，我们将分析前肽对生长因子的生物利用度和组织分布的影响，目的是开发更有效的治疗剂。

Theme: Bioscience for HealthType 2 Diabetes and metabolic diseases more generally together with cardiovascular diseases affect increasing numbers of people. There is interest in regenerative approaches for both pancreaticbeta-cells and cardiomyocytes. TGFbfamily proteins play an important part in cell development and differentiation as well as in disease and BMP2 has been successfully developed and is marketed as a regenerative factor for bone growth. GDNF subfamily of growth factors are normally used as neurotrophic factors, but neurturin in particular has been shown to have beneficial effect on diabetic animals, lowering their glucose levels in insulin dependent manner. While the mechanism for this is unknown, the use of neurturin as therapeutic agent is compromised by its poor pharmacodynamic properties and limited tissue distribution. As neurturin, like all GDNF-like proteins, is synthesised as larger precursors. We have recently shown how activin A has very different properties when complexed with its pro-peptide. We hypothesise that the precursor forms of neurturin are similarly different from the mature protein so far used in the assessment of therapeutic potential. The aim of this project is to produce pre-cursor forms of neurturin and analyse its biochemical, biological and structural activities. At the same time we will analyse the effect of the pro-peptide on the bioavailability and tissue distribution of the growth factor, with an aim of developing more effective therapeutic agents.