Investigating the role of DNA repair mechanisms in the development of age-related podocyte malfunction and its consequence on key organs

研究 DNA 修复机制在年龄相关足细胞功能障碍发展中的作用及其对关键器官的影响

基本信息

项目摘要

For decades, clinicians have recognised that the kidney loses function with age. The elderly exhibit progressive decreases in renal blood flow and glomerular filtration rate. As ageing is a systemic event, affecting all organs, it is difficult to resolve between intrinsic age-related (whose that originate within the kidney) and extrinsic events which are responsible for the loss of renal function. Being able to resolve this issue is key to firstly developing a fully mechanistic understanding of the ageing process in the kidney and secondly developing therapies aimed at improving the quality of patient life.Accumulation of DNA damage is one of the key drivers underpinning age-related organ function decline. We have shown that loss-of-function mutations in key regulator of DNA repair (Excision repair cross-complementation 1, Ercc1) lead to progeria (accelerated ageing) which manifests in loss of kidney function. Recently, we have made the striking finding that attenuation of Activin receptor signalling (using the soluble ligand trap protein sActRIIB) prevented many of the key signs of ageing including preventing proteinuria, maintenance of normal podocyte food processes and glomerular basement membrane morphology. Our findings embody an extraordinary prospect to not only identify the signalling pathway the underpin that age-related decline in kidney function but more notably establish a means of discovering pathways and ultimately the molecules that can prevent renal pathology. In this ground-breaking project, we hypothesise that: The accumulation of DNA mutations in podocytes leads to aberrant Activin signalling that attenuates kidney function and initiates a cascade of inter-organ signalling that leads to systemic perturbations. The aims will be reached using a multidisciplinary approach encompassing tissue, cellular and molecular approaches guided by cutting-edge bio-informatic tools. It is our goal that by the end of the project we will not only develop mechanistic insight into the processes that lead to age-related kidney malfunction but also to identify therapeutic targets as a treatment option.
几十年来,临床医生已经认识到肾脏随着年龄的增长而丧失功能。老年人表现出肾血流量和肾小球滤过率的进行性下降。由于衰老是一种影响所有器官的全身性事件,因此很难在内在年龄相关(其起源于肾脏)和导致肾功能丧失的外在事件之间进行分辨。能够解决这一问题的关键是首先发展一个完整的机制了解肾脏的衰老过程,其次开发旨在提高患者生活质量的治疗方法。DNA损伤的积累是支持与年龄相关的器官功能下降的关键驱动因素之一。我们已经证明,DNA修复关键调节因子(切除修复交叉互补1,Ercc 1)的功能缺失突变导致早衰症(加速衰老),表现为肾功能丧失。最近,我们已经做出了惊人的发现,激活素受体信号传导的衰减(使用可溶性配体陷阱蛋白sActRIIB)防止了许多衰老的关键迹象,包括防止蛋白尿、维持正常的足细胞食物过程和肾小球基底膜形态。 我们的研究结果体现了一个非凡的前景,不仅确定了信号通路的基础,年龄相关的肾功能下降,但更显着的是建立了一种手段,发现途径,并最终分子,可以防止肾脏病理。在这个突破性的项目中,我们假设:足细胞中DNA突变的积累导致异常的激活素信号传导,从而减弱肾功能并启动器官间信号传导的级联反应,从而导致系统性扰动。这些目标将采用多学科方法实现,包括由尖端生物信息学工具指导的组织、细胞和分子方法。我们的目标是,在项目结束时,我们不仅要对导致年龄相关性肾功能障碍的过程进行机械洞察,还要确定治疗靶点作为治疗选择。

项目成果

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Professor Dr. Tobias B. Huber其他文献

Professor Dr. Tobias B. Huber的其他文献

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{{ truncateString('Professor Dr. Tobias B. Huber', 18)}}的其他基金

Modulation of the podocyte actin network
足细胞肌动蛋白网络的调节
  • 批准号:
    241702976
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Chronische Nierenerkrankungen und Altersforschung
慢性肾病与衰老研究
  • 批准号:
    237791083
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Professorships
Center for Glomerular Disease and Aging (CGDA)
肾小球疾病和衰老中心 (CGDA)
  • 批准号:
    208202502
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Heisenberg Fellowships
The Role of mTOR dependent and independent signalling pathways for renal tubular cystogenesis
mTOR 依赖和独立信号通路在肾小管囊肿发生中的作用
  • 批准号:
    77902956
  • 财政年份:
    2008
  • 资助金额:
    --
  • 项目类别:
    Clinical Research Units
Dynamische Podozytenfunktion zur Regulation des Nierenfilters
动态足细胞功能调节肾脏过滤器
  • 批准号:
    26722853
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Independent Junior Research Groups
Mechanismen dynamischer Schlitzmembranfunktionen
动态狭缝膜功能机制
  • 批准号:
    5419511
  • 财政年份:
    2003
  • 资助金额:
    --
  • 项目类别:
    Emmy Noether International Fellowships
Predictors of Somatic Symptom Persistence in Patients With Chronic Kidney Disease (RU SOMACROSS)
慢性肾病患者躯体症状持续的预测因素 (RU SOMACROSS)
  • 批准号:
    460374559
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Units
Combined high-resolution structural and functional characterization of the multi-layered bipartite NEPH-NEPHRIN based slit diaphragm
基于狭缝隔膜的多层二分 NEPH-NEPHRIN 的高分辨率结构和功能综合表征
  • 批准号:
    429077705
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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PfAP2-R介导的PfCRT转录调控在恶性疟原虫对喹啉类药物抗性中的作用及机制研究
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MRC TS Award: Investigating the role of cardiolipin metabolism in mitochondrial DNA replication and mitochondrial division
MRC TS 奖:研究心磷脂代谢在线粒体 DNA 复制和线粒体分裂中的作用
  • 批准号:
    MR/X02363X/1
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    2024
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Investigating the conformational changes of the portal protein that drive DNA packaging in a dsDNA virus
研究双链 DNA 病毒中驱动 DNA 包装的门户蛋白的构象变化
  • 批准号:
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    2023
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    --
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Investigating DNA end-processing during non-homologous end joining
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Origins "R" Us: investigating the role of R-loops in origin-independent DNA replication
起源“R”我们:研究 R 环在独立于起源的 DNA 复制中的作用
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    2746267
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    2022
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Investigating the role of arginine methylation as a critical regulator of DNA replication and genome stability
研究精氨酸甲基化作为 DNA 复制和基因组稳定性关键调节因子的作用
  • 批准号:
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    2022
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Investigating the role of long non-coding RNAs in regulation of DNA methylation
研究长链非编码 RNA 在 DNA 甲基化调节中的作用
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Investigating DNA double-strand break repair mechanisms in mammalian cells
研究哺乳动物细胞中 DNA 双链断裂修复机制
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    10380899
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Investigating PTEN:Ki-67 interaction and its role in DNA damage repair
研究 PTEN:Ki-67 相互作用及其在 DNA 损伤修复中的作用
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