Inhibition of Human Islet Amyloid Polypeptide Aggregation

人胰岛淀粉样多肽聚集的抑制

• 批准号: 10704519
• 负责人: Feng Ding
• 金额: $ 40.68万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704519
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Amyloid Proteins; Amyloidosis; Artificial nanoparticles; Bacterial Infections; Beta Cell; Biological; Cell Death; Cell membrane; Computer Models; Cryoelectron Microscopy; Development; Diabetes Mellitus; Disease; Engineering; Environment; Goals; Human; Immune response; In Vitro; Insulin; Length; Mediating; Membrane; Molecular; Nature; Neurodegenerative Disorders; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Parkinson Disease; Pathologic; Process; Proteins; Research; Risk Factors; Specificity; Structure; System; Therapeutic; Time; Toxic effect; Validation; base; beta pleated sheet; cytotoxicity; design; diabetic; dysbiosis; improved; inhibitor; insight; islet amyloid polypeptide; monomer; nanomedicine; nanoparticle; nanotoxicity; new therapeutic target; novel; novel strategies; peptide hormone; prevent; structural biology

Abstract Amyloid aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell death in type-2 diabetes (T2D). IAPP, a peptide hormone co-secreted with insulin by β-cells, is one of the most amyloidogenic proteins and readily forms amyloid fibrils in vitro. Mounting evidence suggests that inhibition of IAPP aggregation and aggregation-mediated cytotoxicity, our long-term goal, is an attractive therapeutic strategy to prevent β-cell death and stop the progression of diabetic conditions in T2D. With the recent advances of Cryo-EM in Structural Biology, atomic structures of IAPP fibrils have been solved, comprised of parallel in-register β-sheets as the cross-β core. However, due to heterogeneous and transient nature of oligomer intermediates populated during aggregation, many details of the process from isolated monomers to final fibrils are still unknown. With amyloid toxicity likely mediated by direct or indirect interactions with the cell membrane, it is increasingly important to study the aggregation of IAPP in the membrane environment. Increasing evidence also suggests pathological correlations between different amyloid diseases – e.g., T2D is the risk factor of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases; and bacterial amyloids may contribute to the onset of neurodegenerative diseases and diabetes. Cross-interactions between different amyloid proteins at the molecular level might contribute to the pathological correlation between corresponding diseases. We have demonstrated that novel nanoparticles can be engineered to mitigate hIAPP aggregation and cytotoxicity. Despite many advantages including the ability to cross biological barriers, major concerns for nanomedicine development include potential toxicity associated with immune responses and the lack of specificity. In this MIRA renewal application, the PI proposes to continuously uncover molecular mechanisms of IAPP aggregation and to explore novel nanoparticle approaches to inhibit IAPP aggregation and toxicity in the following directions: 1) IAPP aggregation and interactions with the membrane; 2) cross-interactions between hIAPP and other amyloidogenic proteins; and 3) mitigation of IAPP amyloidosis with nanoparticles functionalized by endogenous inhibitors. The PI lab will combine computational modeling with experimental characterization and validation. Computational modeling can help bridge the time and length scale gaps between experimental observations and the underlying molecular systems, providing not only molecular insights to experimental observations but also offering experimentally-testable hypotheses. Such a combined computational and experimental approach can improve research efficiency and shorten discovery cycle. The outcome of the proposed studies will help understand disease mechanisms and discover novel therapeutic targets (Project 1); provide molecular bases for pathological correlations between T2D and other amyloid diseases, and the contribution of bacterial infections and dysbiosis to the onset of T2D (Project 2); and offer new approaches to design anti-amyloid nanoparticles with high specificity and reduced nanotoxicity (Project 3). 1

抽象的 胰岛淀粉样多肽 (IAPP) 的淀粉样蛋白聚集与 2 型糖尿病中的 β 细胞死亡相关 (T2D)，IAPP 是一种由 β 细胞与胰岛素共同分泌的肽激素，是最容易产生淀粉样蛋白的蛋白之一。 并在体外容易形成淀粉样原纤维，越来越多的证据表明抑制 IAPP 聚集和 聚集介导的细胞毒性是我们的长期目标，是预防 β 细胞损伤的一种有吸引力的治疗策略 随着冷冻电镜在 T2D 领域的最新进展，死亡并阻止糖尿病病情的进展。 结构生物学，IAPP 原纤维的原子结构已得到解决，由平行对准的 β-折叠组成 然而，由于低聚物中间体的异质性和瞬态性， 在聚集过程中，从分离的单体到最终原纤维的过程的许多细节仍然未知。 淀粉样蛋白毒性可能是通过与细胞膜直接或间接相互作用介导的，因此越来越多 越来越多的证据也表明，研究 IAPP 在膜环境中的聚集很重要。 不同淀粉样蛋白疾病之间的病理相关性 - 例如，T2D 是神经退行性疾病的危险因素 疾病，包括阿尔茨海默病和帕金森病；细菌淀粉样蛋白可能导致发病 神经退行性疾病和糖尿病之间的交叉相互作用。 分子水平可能有助于相应疾病之间的病理相关性。 新型纳米粒子可以被设计来减轻 hIAPP 聚集和细胞毒性。 尽管有许多优点，包括跨越生物屏障的能力，但纳米医学的主要问题 发展包括与免疫反应相关的潜在毒性和缺乏特异性。 MIRA更新应用，PI提出持续揭示IAPP分子机制 聚集并探索抑制 IAPP 聚集和毒性的新型纳米颗粒方法 以下方向：1) IAPP 聚集以及与膜的相互作用；2) 之间的交叉相互作用； hIAPP 和其他淀粉样蛋白；3) 用纳米颗粒减轻 IAPP 淀粉样变性 PI 实验室将通过内源性抑制剂进行功能化，将计算模型与实验相结合。 表征和验证可以帮助弥合时间和长度尺度的差距。 实验观察和底层分子系统之间，不仅提供分子 对实验观察的见解，同时也提供了这样一个可通过实验检验的假设。 计算和实验方法可以提高研究效率并缩短发现周期。 拟议研究的结果将有助于了解疾病机制并发现新的治疗方法 目标（项目 1）；为 T2D 和其他淀粉样蛋白之间的病理相关性提供分子基础 疾病，以及细菌感染和生态失调对 T2D 发病的影响（项目 2）； 设计具有高特异性和降低纳米毒性的抗淀粉样蛋白纳米颗粒的新方法（项目 3）。 1