Unravelling the tissue-specific geography of protein aggregation in human disease

揭示人类疾病中蛋白质聚集的组织特异性地理

• 批准号: MR/W031515/1
• 负责人: Neil Ranson
• 金额: $ 129.49万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW031515%2F1
• 关键词: Unravelling; tissue; specific; geography; protein

Type 2 diabetes mellitus (T2DM) is a very common, chronic metabolic disorder characterised by high blood glucose, variable insulin resistance and insulin deficiency caused by loss of beta-cell function within pancreatic islets. Aggregation of the peptide hormone hIAPP (human islet amyloid polypeptide) in the pancreas is thought to contribute to beta-cell dysfunction and ultimately failure. hIAPP aggregates into amyloid fibrils via poorly characterized oligomeric species, in and around islets. More than 90% of people with T2DM have pancreatic hIAPP amyloid, but the link between these aggregates and loss of functional beta-cell mass is unclear. We do not currently know the structure of hIAPP amyloid that forms in the body, the precise chemical composition of aggregates, or the cellular components they interact with in and around beta-cells. Crucially, we do not understand how these factors change over time and space, e.g. whether there is a difference in aggregation near to islet microvasculature and if this is linked to the severity of the disease. We will establish a new collaboration between biologists, chemists, clinician scientists and engineers, using a nanopipette to perform localized extractions from human pancreatic tissue samples. This device has the resolution to sample from specific regions of individual cells, allowing us to survey and sample tissue cell-by-cell, assessing e.g. the number and/or structure of aggregates/oligomers in and around islets and their microvasculature. We then aim to establish methodologies to study aggregates extracted from tissue. We will use cryo-electron microscopy to investigate what the structure of these aggregates is and if it changes depending of where they are formed within the tissue. We will also employ mass spectrometry to understand what is the chemical composition of the aggregates and check if they interact with our molecules within the body.Crucially, our discoveries will be integrated into the Quality in Organ Donation (QUOD) biobank, adding all the knowledge we will generate within this project into their whole organ atlas for pancreas. We believe this is really important because it will facilitate the discovery of new mechanisms leading to T2DM and hopefully inform the scientific community on the way to prevent and treat this disease. Also we will be making our results available to the diabetes research community and engage with patients group to maximise the societal impact of our research.This project will therefore establish a new multi-modal, multi-centre team with national and international collaborators, aimed at delivering new molecular insight in diabetes research. It will allow us to integrate researchers with different expertise, but a common, shared goal to understand how, where and in what state hIAPP aggregation occurs in the beta-cells of patients with T2DM.

2型糖尿病(T2 DM)是一种非常常见的慢性代谢性疾病，其特征是高血糖、可变的胰岛素抵抗和由于胰岛内β细胞功能丧失而导致的胰岛素缺乏。多肽激素hIAPP(人胰岛淀粉样多肽)在胰腺中的聚集被认为是导致β细胞功能障碍和最终失败的原因。HIAPP在胰岛内和胰岛周围通过特征不佳的低聚物聚集成淀粉样纤维。超过90%的T2 DM患者患有胰腺hIAPP淀粉样蛋白，但这些聚集物与功能性β细胞团丢失之间的联系尚不清楚。我们目前还不知道在体内形成的hIAPP淀粉样蛋白的结构，聚集体的确切化学成分，或者它们在β细胞内和周围相互作用的细胞成分。关键是，我们不知道这些因素是如何随时间和空间变化的，例如，胰岛微血管附近的聚集是否存在差异，以及这是否与疾病的严重程度有关。我们将在生物学家、化学家、临床科学家和工程师之间建立一种新的合作，使用纳米管从人类胰腺组织样本中进行局部提取。该设备具有从单个细胞的特定区域采样的分辨率，使我们能够逐个细胞地测量和采样组织细胞，评估例如胰岛及其周围的聚集体/低聚物及其微血管的数量和/或结构。然后，我们的目标是建立研究从组织中提取的聚集体的方法。我们将使用冷冻电子显微镜来研究这些聚集体的结构是什么，以及它是否会随着它们在组织中形成的位置而变化。我们还将使用质谱仪来了解聚集体的化学成分，并检查它们是否与我们体内的分子相互作用。关键是，我们的发现将被整合到器官捐赠质量(QUOD)生物库中，将我们在这个项目中产生的所有知识添加到他们的整个胰腺器官图谱中。我们相信这真的很重要，因为它将促进发现导致T2 DM的新机制，并有望向科学界通报预防和治疗这种疾病的方法。此外，我们还将把我们的成果提供给糖尿病研究社区，并与患者群体接触，以最大限度地发挥我们研究的社会影响。因此，该项目将建立一个新的多模式、多中心团队，与国内和国际合作者合作，旨在提供糖尿病研究的新分子见解。这将使我们能够将拥有不同专业知识的研究人员整合在一起，但有一个共同的目标，即了解hIAPP在T2 DM患者的β细胞中如何、在哪里和在什么状态下发生聚集。