Developing a human vascularised pancreatic islet on a chip - VIOC

在芯片上开发人类血管化胰岛 - VIOC

• 批准号: NC/X002365/1
• 负责人: Victoria Salem
• 金额: $ 25.78万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FX002365%2F1
• 关键词: Developing; human; vascularised; pancreatic; islet

Maintaining blood sugar levels within a remarkably narrow range despite large variations in how much we eat or exercise is one of the marvels of the human body. Two hormones each with opposing effects, glucagon and insulin, are the main regulators of blood sugar. They are released from tiny "islets" that are dispersed throughout the pancreas. Islet cells constantly sense sugar levels in the blood and respond in a finely tuned manner to release the right mix of insulin and glucagon to tightly control our blood sugar levels. There remain fundamental gaps in our understanding of how islets work in healthy people to regulate blood sugar. Furthermore, discovering how to restore these mechanisms in patients with diabetes, now affecting over 1 in 11 adults, is essential if we are to find a cure for the disease.We have recently shown that the hormone secreting cells within the islets are connected and communication between them is essential for orchestrating healthy insulin release. To date most of our understanding about islet function comes from rodent studies, since human islets are too small to radiologically image and the pancreas is too deep and dangerous to biopsy. However, the relative positions of the different hormone-secreting cell types differs quite markedly between human and rodent islets and the blood circulation is different too. This limits our ability to make conclusions about human islet function from rodent studies. Some labs are able to perform experiments on islets donated to medical research by people who have died. However, in a petri dish with culture medium these precious islets quickly die. We are unable re-create the important element of blood flow through capillaries within the islet that carry in nutrients (like sugar) and pass on important hormonal messages within the islet itself and beyond. Therefore the aim of this project is to extend the life and utility of donor human islets in a device that supports the islets to become embedded and ultimately vascularised in a bed of human capillaries. This "vascularised islet on a chip" or VIOC will allow us to circulate nutrients through the blood vessel network and through the islet, keeping it alive for much longer than is now possible. The chip will be transparent so that we can examine the responses of human islets under the microscope in real-time and it can also be linked to hormone measuring devices to achieve readouts of hormone secretory function. VIOC will allow us to study human islet function in response to a range of experiments that could help us answer fundamental questions that are still unknown - for example whether specific nutrients (breakdown products of fat or protein metabolism) have particular benefits on insulin secretion or how the immune system interacts with islets to protect them from damage. We will work with our network of collaborators in the field of islet biology to validate VIOC as an effective and indeed superior replacement for rodents to interrogate islet function in health and disease.

尽管我们的饮食或运动量存在很大差异，但血糖水平仍保持在非常狭窄的范围内，这是人体的奇迹之一。胰高血糖素和胰岛素是血糖的主要调节剂，这两种激素的作用相反。它们从分散在整个胰腺中的微小“胰岛”中释放出来。胰岛细胞不断感知血液中的血糖水平，并以微调的方式做出反应，释放胰岛素和胰高血糖素的正确组合，以严格控制我们的血糖水平。在我们对健康人的胰岛如何调节血糖的理解方面仍然存在根本性的差距。此外，如果我们要找到治愈糖尿病的方法，那么发现如何在糖尿病患者中恢复这些机制是至关重要的。糖尿病患者现在影响超过1/11的成年人。我们最近表明，胰岛内的激素分泌细胞是连接的，它们之间的通信对于协调健康的胰岛素释放至关重要。迄今为止，我们对胰岛功能的了解大多来自啮齿动物的研究，因为人类胰岛太小，无法进行放射成像，而胰腺太深，活检太危险。然而，不同类型的胰岛分泌细胞的相对位置在人类和啮齿类动物的胰岛之间存在显著差异，并且血液循环也不同。这限制了我们从啮齿动物研究中得出关于人类胰岛功能的结论的能力。一些实验室能够在已经去世的人捐赠给医学研究的胰岛上进行实验。然而，在培养皿中，这些珍贵的胰岛很快就会死亡。我们无法重新创造通过胰岛内毛细血管的重要血液流动元素，这些元素携带营养物质（如糖）并在胰岛本身内外传递重要的激素信息。因此，该项目的目的是延长供体人胰岛在支持胰岛嵌入并最终在人毛细血管床中血管化的装置中的寿命和效用。这种“芯片上的血管化胰岛”或VIOC将使我们能够通过血管网络和胰岛循环营养物质，使其存活时间比现在更长。芯片将是透明的，这样我们就可以在显微镜下实时检查人体胰岛的反应，它也可以连接到激素测量设备，以实现激素分泌功能的读数。VIOC将使我们能够研究人类胰岛功能，以响应一系列实验，这些实验可以帮助我们回答仍然未知的基本问题-例如特定营养素（脂肪或蛋白质代谢的分解产物）是否对胰岛素分泌有特别的好处，或者免疫系统如何与胰岛相互作用以保护它们免受损害。我们将与胰岛生物学领域的合作者网络合作，验证VIOC作为啮齿动物在健康和疾病中询问胰岛功能的有效且确实上级替代品。