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）的构象怀疑参与II型糖尿病的病理。该研究将开始，用所采用的仪器来指导研究学生，以有效地理解可以在各种溶剂和不同条件下形成的胰淀素的动态前原纤维构象，以获得对无序蛋白质的内在性质及其在原纤维和非原纤维途径上采用的不同结构的理解。聚集中间体已经被鉴定，工作将继续鉴定如何通过分析潜在的小分子结合配偶体将胰淀素从假定的病理性聚集途径引导到非聚集途径（其可以在工作台上利用有机合成方法来设计），肽（可以使用合成生物学方法培养）这项研究将理想地为聚集中间体的新型抑制剂铺平道路，这些聚集中间体被鉴定为与II型糖尿病的病理学有关的细胞毒性剂，试管承诺在评估有希望的化合物的药代动力学/药效学参数和可药用性以及次级药理学的任何潜力后，可能有可能使用表达人胰淀素的转基因鼠品系在体内测试化合物，其中可以在对照和化合物处理的批次中诱导II型糖尿病表型，以评估新型抑制剂的作用。

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.