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

基本信息

  • 批准号:
    MR/T032251/1
  • 负责人:
  • 金额:
    $ 42.22万
  • 依托单位:
  • 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

项目摘要

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.
糖尿病是一个重大的公共卫生问题,目前全球患病率估计为 8.8%,并且由于人口老龄化和肥胖症的增加而不断上升。糖尿病的治疗给医疗资源带来了巨大压力。英国 NHS 预算的 10% 用于治疗糖尿病,而在加拿大,2012-22 年间诊断的新糖尿病病例的费用估计为 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而产生的,例如肾病、失明、心脏病、中风和下肢截肢。这些通常是由脉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确定了几种保护糖尿病脉管系统的候选分子。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体类器官来模拟糖尿病,在这一领域取得了关键突破。这些类器官发表在《自然》杂志(2019 年)上,源自人类干细胞,然后将其暴露于生长因子环境中以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体内会导致结构变化,类似于糖尿病患者中观察到的血管变化。基因表达谱揭示了当血管类器官暴露于高血糖时,血管中的分子途径发生了改变。其中之一是血管生成素-2,它可以调节血管生长和炎症,并已被证明可以在糖尿病肾病小鼠模型中导致血管功能障碍。第二种是 apelin,一种肽,其阻断已被证明可以减少肿瘤生长。该提案将基于这些发现,通过使用人体血管类器官来检查血管生成素-2 或 apelin 的阻断是否可以预防高血糖引起的人体血管变化类器官系统(目标 1)。其次,我们将使用复杂的动物模型来研究血管中的 angiopoietin-2 (Aim 2) 和 apelin (Aim 3) 如何精确影响糖尿病血管并发症。最后,我们使用人体血管类器官系统来了解为什么一些患者能够免受糖尿病血管并发症的影响(目标 4)。为此,我们将使用有/无蛋白尿病史(受保护或易患肾脏血管疾病)的 1 型糖尿病患者的血清样本,蛋白尿是血管损伤的一般标志。我们将把人体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,我们将使用无偏蛋白质组学来评估血清的成分,以确定预防糖尿病血管损伤的保护因素。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apelin 作为糖尿病血管并发症的治疗方法。我们预测,使用患有/不患有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

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Identification of an Altered Matrix Signature in Kidney Aging and Disease.
肾脏衰老和疾病中改变的矩阵特征的鉴定。
  • DOI:
    http://dx.10.1681/asn.2020101442
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Randles MJ
  • 通讯作者:
    Randles MJ
Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder.
实验性长期糖尿病会改变大鼠膀胱的转录组和生物力学特性。
  • DOI:
    http://dx.10.1038/s41598-021-94532-7
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Hindi EA
  • 通讯作者:
    Hindi EA
Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies.
糖尿病肾病:从机制到临床表现和治疗策略。
  • DOI:
    http://dx.10.1016/j.metabol.2021.154890
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ricciardi CA
  • 通讯作者:
    Ricciardi CA
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:
    http://dx.10.1038/s41467-024-45710-4
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Quintard C
  • 通讯作者:
    Quintard C
Kidney organoids recapitulate human basement membrane assembly in health and disease.
肾脏类器官概括了健康和疾病状态下的人类基底膜组装。
  • DOI:
    http://dx.10.7554/elife.73486
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Morais MRPT
  • 通讯作者:
    Morais MRPT
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David Long其他文献

Informing the Debate
为辩论提供信息
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Richard Hula;David Long;Thomas C. Voice
  • 通讯作者:
    Thomas C. Voice
The maize transposable element system Ac/Ds as a mutagen in Arabidopsis: identification of an albino mutation induced by Ds insertion.
玉米转座元件系统 Ac/Ds 作为拟南芥诱变剂:鉴定 Ds 插入诱导的白化突变。
Stress-related changes to immune cells in the skin prior to wounding may impair subsequent healing
受伤前皮肤中与压力相关的免疫细胞变化可能会损害随后的愈合
  • DOI:
    10.1016/j.bbi.2015.06.011
  • 发表时间:
    2015-11-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    H. Koschwanez;M. Vurnek;J. Weinman;J. Tarlton;C. Whiting;Satya Amirapu;Sarah Colgan;David Long;P. Jarrett;E. Broadbent
  • 通讯作者:
    E. Broadbent
Factors Influencing Medication Errors in the Prehospital Paramedic Environment: A Mixed Method Systematic Review
院前护理人员环境中影响用药错误的因素:混合方法系统评价
  • DOI:
    10.1080/10903127.2022.2068089
  • 发表时间:
    2022-05-17
  • 期刊:
  • 影响因子:
    2.4
  • 作者:
    Dennis Walker;Clint Moloney;B. SueSee;Renee Sharples;Rosanna Blackman;David Long;X. Hou
  • 通讯作者:
    X. Hou
Mechanical and electromechanical devices
机械和机电设备
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    D. Cowan;Martin D. Smith;Vicky Gardiner;P. Horwood;Christopher Morris;T. Holsgrove;Tori Mayhew;David Long;M. Hillman
  • 通讯作者:
    M. Hillman

David Long的其他文献

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{{ truncateString('David Long', 18)}}的其他基金

RII Track-4: NSF: Developing 3D Models of Live-Endothelial Cell Dynamics with Application Appropriate Validation
RII Track-4:NSF:开发活内皮细胞动力学的 3D 模型并进行适当的应用验证
  • 批准号:
    2327466
  • 财政年份:
    2024
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Standard Grant
RII Track-4: NSF: Developing 3D Models of Live-Endothelial Cell Dynamics with Application Appropriate Validation
RII Track-4:NSF:开发活内皮细胞动力学的 3D 模型并进行适当的应用验证
  • 批准号:
    2327466
  • 财政年份:
    2024
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Standard Grant
How do weak shocks accelerate high energy particles?
弱激波如何加速高能粒子?
  • 批准号:
    ST/R003246/2
  • 财政年份:
    2023
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Fellowship
Using microinjections and flow to enhance maturation of blood vessel organoids into regenerative medicine tools
使用显微注射和流动促进血管类器官成熟为再生医学工具
  • 批准号:
    MR/X503113/1
  • 财政年份:
    2022
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Research Grant
Collaborative Research: Investigating STEM Teacher Preparation and Rural Teacher Persistence and Retention
合作研究:调查 STEM 教师准备和农村教师的坚持和保留
  • 批准号:
    2050095
  • 财政年份:
    2021
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Standard Grant
How do weak shocks accelerate high energy particles?
弱激波如何加速高能粒子?
  • 批准号:
    ST/R003246/1
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Fellowship
Preparing Secondary Teachers of Mathematics and Science in Rural Districts
培养农村中学数学和科学教师
  • 批准号:
    1660721
  • 财政年份:
    2017
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Continuing Grant
Investigating the renal microvasculature in polycystic kidney disease
研究多囊肾病的肾脏微血管系统
  • 批准号:
    MR/P018629/1
  • 财政年份:
    2017
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Research Grant
North Sea Interactive: A decision-support tool to guide environmental monitoring by the oil and gas industry
North Sea Interactive:指导石油和天然气行业环境监测的决策支持工具
  • 批准号:
    NE/L008181/1
  • 财政年份:
    2014
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Research Grant
The role of podocyte thymosin-beta4 in the healthy and diseased glomerulus
足细胞胸腺素-β4 在健康和患病肾小球中的作用
  • 批准号:
    MR/J003638/1
  • 财政年份:
    2012
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Research Grant

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不确定性与核心技术差距双重约束下内需变动对外贸稳定性与韧性的影响研究
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相似海外基金

Bridging the gap to translation by understadning and preventing diabetic vascular complications using human organoid culture (MRC NPI: David Andrew Long)
通过使用人类类器官培养了解和预防糖尿病血管并发症来缩小翻译差距(MRC NPI:David Andrew Long)
  • 批准号:
    410862
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
    Operating Grants
Bridging the evidence-to-practice gap: Evaluating practice facilitation as a strategy to accelerate translation of a systems-level adherence intervention into safety net practices
弥合证据与实践之间的差距:评估实践促进作为加速将系统级依从性干预转化为安全网实践的策略
  • 批准号:
    10253671
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
Bridging the evidence-to-practice gap: Evaluating practice facilitation as a strategy to accelerate translation of a systems-level adherence intervention into safety net practices
弥合证据与实践之间的差距:评估实践促进作为加速将系统级依从性干预转化为安全网实践的策略
  • 批准号:
    10536608
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
Bridging the evidence-to-practice gap: Evaluating practice facilitation as a strategy to accelerate translation of a systems-level adherence intervention into safety net practices
弥合证据与实践之间的差距:评估实践促进作为加速将系统级依从性干预转化为安全网实践的策略
  • 批准号:
    10403758
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
Bridging the evidence-to-practice gap: Evaluating practice facilitation as a strategy to accelerate translation of a systems-level adherence intervention into safety net practices
弥合证据与实践之间的差距:评估实践促进作为加速将系统级依从性干预转化为安全网实践的策略
  • 批准号:
    10303004
  • 财政年份:
    2019
  • 资助金额:
    $ 42.22万
  • 项目类别:
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