Bridging the gap to translation by understanding and preventing diabetic vascular complications using human organoids

通过使用人体类器官了解和预防糖尿病血管并发症来缩小翻译差距

• 批准号: MR/T032251/1
• 负责人: David Long
• 金额: $ 42.22万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT032251%2F1
• 关键词: Bridging; gap; translation; understanding; preventing

Diabetes is a major public health issue with current global prevalence estimated at 8.8% and rising due to the aging population and increasing obesity. The treatment of diabetes is putting a high strain on healthcare resources. 10% of the UK NHS budget is spent on treating diabetes, whilst in Canada the cost of new cases of diabetes diagnosed between 2012-22 is estimated at $15.4 billion. Many of these healthcare costs are due to treating complications associated with diabetes such as kidney disease, blindness, heart attacks, stroke and amputation of lower limbs. These are often caused by changes in the vasculature, therefore, strategies which protect or repair blood vessels have the potential to be new therapies for diabetic patients. Studies using murine models and cultured cells have identified several candidate molecules which protect the diabetic vasculature. However, the challenge is to translate these findings into the clinical setting. For this, we need appropriate experimental models to bridge the gap between rodents and clinical trials.The research team on this proposal has made a key breakthrough in this area by developing vascular human organoids to model diabetes. Published in Nature (2019), these organoids are derived from human stem cells which are then exposed to a milieu of growth factors to assemble into capillary networks. Exposure of the organoid to high glucose or their transplantation into mice which are subsequently made diabetic leads to structural changes which mimic the changes to blood vessels seen in diabetic patients. Gene expression profiling has revealed molecular pathways altered in the blood vessels when the vascular organoid is exposed to hyperglycaemia. One of these is angiopoietin-2, which modulates blood vessel growth and inflammation and has been shown to drive vascular dysfunction in a murine model of diabetic kidney disease. The second is apelin, a peptide whose blockade has been shown to reduce tumor growth.This proposal will build on these findings by using the human vascular organoid to examine if blockade of angiopoietin-2 or apelin can prevent the hyperglycaemia induced changes in the human vessel organoid system (Aim 1). Secondly, we will use sophisticated animal models to work out how both angiopoietin-2 (Aim 2) and apelin (Aim 3) in blood vessels precisely effects diabetic vascular complications. Finally, we use the human vessel organoid system to understand why some patients are protected from diabetic vascular complications (Aim 4). To do this, we will use serum samples from type 1 diabetic patients with/without history of albuminuria (protected or susceptible towards the development of vascular disease in their kidneys), a general marker for blood vessel damage. We will expose the human vessel organoids to serum from these two groups of patients and examine changes in organoid structure, cellular composition and gene profile. Finally, we will use non-biased proteomics to assess the composition of the serum to identify protective factors which prevent blood vessel damage in diabetes.Collectively, our proposal will bridge the gap between rodent studies and clinical trials and test the potential of manipulating angiopoietins and apelin as a therapy for diabetic vascular complications. We predict that using samples from diabetic patients with/without albuminuria will facilitate the discovery of new therapeutic targets to treat diabetic complications in the future.

糖尿病是一个主要的公共卫生问题，目前全球患病率估计为8.8%，并且由于人口老龄化和肥胖增加而不断上升。糖尿病的治疗给医疗资源带来了很大的压力。英国NHS预算的10%用于治疗糖尿病，而在加拿大，2012-22年间诊断出的糖尿病新病例的费用估计为154亿美元。其中许多医疗费用是由于治疗与糖尿病相关的并发症，如肾脏疾病，失明，心脏病发作，中风和下肢截肢。这些通常是由血管系统的变化引起的，因此，保护或修复血管的策略有可能成为糖尿病患者的新疗法。使用小鼠模型和培养细胞的研究已经鉴定了几种保护糖尿病血管的候选分子。然而，挑战是将这些发现转化为临床环境。为此，我们需要合适的实验模型来弥合啮齿动物和临床试验之间的差距。该提案的研究团队通过开发血管人类类器官来模拟糖尿病，在这一领域取得了关键突破。这些类器官来源于人类干细胞，然后暴露于生长因子的环境中组装成毛细血管网络。将类器官暴露于高葡萄糖或将其移植到随后患糖尿病的小鼠中导致结构变化，其模拟糖尿病患者中所见的血管变化。基因表达谱显示，当血管类器官暴露于高脂血症时，血管中的分子通路发生改变。其中之一是血管生成素-2，它调节血管生长和炎症，并已被证明在糖尿病肾病小鼠模型中驱动血管功能障碍。第二种是apelin，一种其阻断已被证明可减少肿瘤生长的肽。该提议将基于这些发现，通过使用人血管类器官来检查血管生成素-2或apelin的阻断是否可以防止高血压诱导的人血管类器官系统的变化（Aim 1）。其次，我们将使用复杂的动物模型来研究血管中的血管生成素-2（Aim 2）和爱帕琳肽（Aim 3）如何精确地影响糖尿病血管并发症。最后，我们使用人类血管类器官系统来理解为什么一些患者免受糖尿病血管并发症的影响（目的4）。为此，我们将使用来自有/无蛋白尿史的1型糖尿病患者的血清样本（受保护或易发生肾脏血管疾病），这是血管损伤的一般标志物。我们将人类血管类器官暴露于这两组患者的血清中，并检查类器官结构，细胞组成和基因谱的变化。最后，我们将使用无偏见的蛋白质组学来评估血清的组成，以确定预防糖尿病血管损伤的保护因子。总的来说，我们的建议将弥合啮齿动物研究和临床试验之间的差距，并测试操纵血管生成素和爱帕琳作为糖尿病血管并发症治疗的潜力。我们预测，使用来自有/无蛋白尿的糖尿病患者的样本将有助于发现未来治疗糖尿病并发症的新治疗靶点。

项目成果

Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder.

• DOI: 10.1038/s41598-021-94532-7
• 发表时间: 2021-07-30
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hindi EA;Williams CJ;Zeef LAH;Lopes FM;Newman K;Davey MMM;Hodson NW;Hilton EN;Huang JL;Price KL;Roberts NA;Long DA;Woolf AS;Gardiner NJ
• 通讯作者: Gardiner NJ

Kidney organoids recapitulate human basement membrane assembly in health and disease.

• DOI: 10.7554/elife.73486
• 发表时间: 2022-01-25
• 期刊: eLife
• 影响因子: 7.7
• 作者: Morais MRPT;Tian P;Lawless C;Murtuza-Baker S;Hopkinson L;Woods S;Mironov A;Long DA;Gale DP;Zorn TMT;Kimber SJ;Zent R;Lennon R
• 通讯作者: Lennon R

A microfluidic platform integrating functional vascularized organoids-on-chip

集成功能性血管化类器官芯片的微流控平台

• DOI: 10.1038/s41467-024-45710-4
• 发表时间: 2024
• 期刊: Nature Communications
• 影响因子: 16.6
• 作者: Quintard C