功能分子调控淀粉样多肽组装结构及其力学性能

发布时间：2018-04-25 17:12

本文选题：hIAPP20-29 + 胰岛淀粉样多肽聚集　；参考：《江苏大学》2017年硕士论文

【摘要】：淀粉样多肽的错误折叠与多种退行性疾病的致病机制密切相关,例如:阿兹海默氏病、帕金森病、II-型糖尿病、亨廷顿病。而其中,II-型糖尿病,也被称作非胰岛素依赖型糖尿病,是糖尿病最常见方式的一种,约占患者人数的90%以上。找到糖尿病的有效治疗或者控制方法是目前急需解决的重要问题。胰岛淀粉样多肽是一段包含有37个氨基酸残基的多肽链,研究表明,其形成的淀粉样在胰岛的沉积与II-型糖尿病的发病有着密不可分的联系。H2NSNNFGILSS-COOH(hIAPP20-29)是胰岛淀粉样多肽成纤维的核心片段,因此研究如何调控这段十个氨基酸的短肽序列的聚集,对于寻找有效治疗II-型糖尿病的方法具有重要的指导意义。在本文中,我们利用光驱动卟啉分子成功地抑制了hIAPP20-29的自聚集以及降解了其自聚集形成的淀粉样纤维。并结合DCF荧光、PeakForce Quantitative Nanoscale Mechanical和UV光谱对其调控机理进行了合理的推测。这一发现对以后设计新的调控胰岛淀粉样多肽聚集的方法提供了一定的指导意义,同时也丰富了抑制剂的选择。具体的研究内容如下:(1)我们利用圆二色谱(circular dichroism,CD)、Thioflavin T荧光标记以及原子力显微镜(AFM)技术,对hIAPP20-29自聚集的过程,二级结构的变化,以及聚集体形貌演变进行了表征分析。(2)系统的研究了光照、卟啉分子、光驱动卟啉分子以及其浓度变化对于调控胰岛淀粉样多肽聚集形貌及其力学性质的影响。结果表明光驱动卟啉分子可以有效地抑制hIAPP20-29的聚集,其形貌以及二级结构的变化受卟啉分子浓度的影响,发生从短纤维到膜状结构和β-折叠到无规卷曲的转变。其结构的杨氏模量随着卟啉分子浓度的提高逐渐增强,说明卟啉参与了多肽的自组装过程。Dichlorofluorescein光谱以及UV光谱测试表明了光刺激条件下的卟啉分子产生的ROS破坏了多肽链之间氢键的相互作用,从而破坏了原有的自组装过程,而且光驱动卟啉分子抑制效果在无持续光照刺激下具有持续抑制作用。(3)利用光驱动卟啉分子进一步的降解了成熟的淀粉样多肽纤维表明光驱动卟啉分子具有降解成熟纤维的效果。
[Abstract]:Misfolding of amyloid peptides is closely related to the pathogenesis of a variety of degenerative diseases, such as Aziz Heimo S's, Parkinson's, type II-, and Huntington's disease. Among them, type II- diabetes, also known as non insulin dependent diabetes, is one of the most common ways of diabetes, accounting for about 90% of the number of patients. To find diabetes. The effective treatment or control method of disease is an important problem to be solved urgently. Islet amyloid polypeptide is a polypeptide chain containing 37 amino acid residues. The study shows that the deposition of amyloid in the islets of the pancreas is inextricably linked to the onset of type II- diabetes.H2NSNNFGILSS-COOH (hIAPP20-29) is the amyloid islet like It is important to study how to regulate the aggregation of short peptide sequences of the ten amino acids, which is of great significance for the search for the effective treatment of II- type diabetes. In this paper, we successfully inhibit the self aggregation of hIAPP20-29 and degrade its self aggregation by using light driven porphyrin molecules. The regulatory mechanism of the amyloid fibers, combined with DCF fluorescence, PeakForce Quantitative Nanoscale Mechanical and UV spectra, has been reasonably speculated. This discovery provides a certain guiding significance for the design of a new method of regulating the aggregation of islet amyloid peptides in the future, and is also rich in the selection of the inhibitors. (1) (1) we used circular two chromatography (circular dichroism, CD), Thioflavin T fluorescence labeling and atomic force microscopy (AFM) to characterize the self aggregation of hIAPP20-29, the changes in the two structure and the evolution of the aggregate morphology. (2) the system has studied the illumination, porphyrin, light driven porphyrin and its concentration change. The effects on the morphology and mechanical properties of the islet amyloid peptides are regulated. The results show that the porphyrin molecules can effectively inhibit the aggregation of hIAPP20-29. The changes of the morphology and the structure of the two stage are influenced by the molecular concentration of porphyrin, and the structure of the transition from short fiber to membranous structure and beta fold to random curl. The young's modulus increases with the increase of the molecular concentration of porphyrin, indicating that porphyrin participates in the.Dichlorofluorescein spectrum of the self-assembly process of the polypeptide and the UV spectrum test shows that the ROS produced by the porphyrin molecule under the condition of light stimulation destroys the interaction between the hydrogen bonds between the polypeptide chains, thus destroying the original self-assembly process and the light. The inhibition effect of porphyrin driven molecules was sustained under no sustained light stimulation. (3) the effect of porphyrin molecules with mature amyloid peptide fiber was further degraded by light driven porphyrin molecules to drive porphyrin molecules to degrade mature fibers.

【学位授予单位】：江苏大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R587.1

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