Developing a human vascularised pancreatic islet on a chip - VIOC

尽管我们的饮食或运动量差异很大，但仍能将血糖水平保持在一个非常窄的范围内，这是人类身体的奇迹之一。两种各有相反作用的荷尔蒙--胰升糖素和胰岛素--是血糖的主要调节剂。它们从分散在整个胰腺的微小“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，释放正确的胰岛素和胰高血糖素组合，以严格控制我们的血糖水平。在我们对胰岛如何在健康人中调节血糖的理解上仍然存在根本性的差距。此外，如果我们要找到治疗糖尿病的方法，发现如何恢复糖尿病患者的这些机制是至关重要的。糖尿病患者现在每11个成年人中就有1人受到影响。我们最近表明，胰岛内的激素分泌细胞是相互连接的，它们之间的沟通对于协调健康的胰岛素释放是必不可少的。到目前为止，我们对胰岛功能的了解大多来自啮齿动物的研究，因为人类的胰岛太小，无法进行放射成像，而胰腺太深，太危险，无法进行活组织检查。然而，不同激素分泌细胞类型在人和啮齿动物胰岛中的相对位置有很大差异，血液循环也不同。这限制了我们从啮齿动物研究中得出人类胰岛功能的结论。一些实验室能够对死者捐赠给医学研究的胰岛进行实验。然而，在装有培养介质的培养皿中，这些珍贵的胰岛很快就会死亡。我们无法通过胰岛内的毛细血管重建血液流动的重要元素，这些毛细血管携带营养物质(如糖)，并在胰岛内外传递重要的荷尔蒙信息。因此，该项目的目的是在一种设备中延长供体人类胰岛的寿命和用途，以支持胰岛嵌入并最终在人类毛细血管床中形成血管。这种“芯片上的血管胰岛”或VIOC将允许我们通过血管网络和胰岛循环营养物质，使其存活的时间比现在可能的要长得多。该芯片将是透明的，这样我们就可以在显微镜下实时检查人类胰岛的反应，它还可以连接到激素测量设备，实现激素分泌功能的读数。VIOC将允许我们通过一系列实验来研究人类胰岛的功能，这些实验可以帮助我们回答尚不清楚的基本问题-例如，特定的营养物质(脂肪或蛋白质代谢的分解产物)是否对胰岛素分泌有特殊好处，或者免疫系统如何与胰岛相互作用以保护它们免受损害。我们将与我们在胰岛生物学领域的合作伙伴网络合作，验证VIOC是一种有效的、甚至是优越的啮齿动物替代品，用于询问胰岛在健康和疾病中的功能。

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.