Developing a new class of anti-amyloid experimental therapeutics in diabetes

该研究项目围绕着表征胰淀素(IAPP)的构象，怀疑其参与了II型糖尿病的病理过程。研究将首先让研究学生熟悉用于有效理解在不同溶剂和不同条件下可以形成的淀粉蛋白的动态前纤维构象的仪器，以获得对无序蛋白质的内在本质及其在纤维和非纤维途径上采用的不同结构的评价。一旦确定了聚集和非聚集中间体的构象，将继续工作，通过分析潜在的小分子结合伙伴(可以利用在工作台上的有机合成方法来设计)，确定如何将胰淀素从假设的病理性聚集途径引导到非聚集途径，多肽(可以用合成生物学方法培养)和其他利用MS技术的实体。这项研究将理想地为新型聚集中间体抑制剂铺平道路，这些中间体被确定为与II型糖尿病的病理有关的细胞毒剂，首次具有体外前景。在评估了有希望的化合物(S)的药代动力学/药效学参数和可药性以及任何二次药理学的可能性后，可能有可能前进到使用表达人胰淀素的转基因小鼠品系在体内测试该化合物，其中可能会在对照和复方治疗批次中诱导II型糖尿病表型，以评估这种新型抑制剂的效果。

The research project revolves around characterising the conformations of Amylin (IAPP) suspected of being involved within the pathology of Type II Diabetes. The research will begin with acquainting the research student with the instrumentation employed to effectively understand the dynamic pre-fibrillar conformers of amylin that can form under various solvents and differing conditions to gain an appreciation of the intrinsic nature of the disordered protein and the different structures it adopts on both fibrillar and non-fibrillar pathways.Once the conformations of aggregation and non-aggregation intermediates have been identified, work will proceed to identify how to direct Amylin from the supposed pathological aggregation pathway toward the non-aggregation pathway via the analysis of potential small molecule binding partners (which may be designed utilising organic synthesis approaches at the bench), peptides (which may be cultivated using synthetic biology methods) and other entities utilising MS techniques.This research will ideally pave the way toward novel inhibitors for aggregation intermediates identified as the cytotoxic agents implicated in the pathology of Type II Diabetes firstly with in vitro promise. After assessing the promising compound(s) pharmacokinetic/pharmacodynamic parameters and druggability as well as any potential for secondary pharmacology, there may be potential to move forward to testing the compound in vivo using a transgenic murine strain expressing human Amylin, where a Type II Diabetic phenotype may be induced in control and compound treated batches to assess the effects of the novel inhibitor.