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，目前的全球患病率估计为8.8％，并且由于人口老龄化和肥胖症的增加而增加。糖尿病的治疗对医疗资源产生了很大的压力。英国NHS预算的10％用于治疗糖尿病，而在加拿大，2012 - 22年间诊断出的新糖尿病的成本估计为154亿美元。这些医疗保健费用中有许多是由于治疗与肾脏疾病，失明，心脏病发作，中风和下肢截肢相关的并发症所致。这些通常是由脉管系统变化引起的，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。使用鼠模型和培养细胞的研究已经确定了几个保护糖尿病脉管系统的候选分子。但是，挑战是将这些发现转化为临床环境。为此，我们需要适当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体器官来建模糖尿病，在该领域取得了关键的突破。这些类器官在自然界发表（2019年）中是从人类干细胞中得出的，然后将其暴露于生长因子的环境中，以聚集到毛细血管网络中。类器官暴露于高葡萄糖或将其移植到小鼠中，随后使糖尿病导致结构性变化，这些变化模仿了糖尿病患者中血管的变化。基因表达谱分析表明，当血管器官暴露于高血糖时，血管中的分子途径改变了。其中之一是Angiopoietin-2，它调节血管生长和炎症，并已显示在糖尿病肾脏疾病的鼠模型中驱动血管功能障碍。第二个是Apelin，这是一种肽，其封锁已被证明可以减少肿瘤的生长。该提案将通过使用人血管器官来基于这些发现的基础，以检查封锁Angiopoietin-2或Apelin是否可以防止高血糖诱导的人体器官系统变化（AIM 1）。其次，我们将使用复杂的动物模型来确定血管中血管蛋白2（AIM 2）和Apelin（AIM 3）如何精确影响糖尿病血管并发症。最后，我们使用人体血管器官系统来了解为什么某些患者免受糖尿病血管并发症的影响（AIM 4）。为此，我们将使用来自/没有/没有蛋白尿病史的1型糖尿病患者的血清样本（受到肾脏中血管疾病的发展），这是血管损害的一般标志。我们将从这两组患者的血清中暴露于人体血管，并检查器官结构，细胞组成和基因谱的变化。最后，我们将使用无偏的蛋白质组学评估血清的组成，以鉴定防止血管损害糖尿病的血管损害的保护因子。进行填充，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apelin作为糖尿病血管血管血管血管血管血管血管血管血管的治疗的潜力。我们预测，使用/不含蛋白尿的糖尿病患者的样本将促进发现新的治疗靶标在将来治疗糖尿病并发症。

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