DECIPHERING ROLES OF GDNF-GFRA1 RET SIGNALING IN NORMAL AND INJURED KIDNEY

解读 GDNF-GFRA1 RET 信号在正常和受损肾脏中的作用

基本信息

  • 批准号:
    8019438
  • 负责人:
  • 金额:
    $ 25.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-02-20 至 2012-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Congenital, chronic and acute kidney diseases cause significant morbidity, mortality and economic burden to our society. A significant impact in all these areas will be made by identifying pathogenetic mechanisms that cause kidney diseases. Because humans and mice share a number of characteristics of kidney development and function, and animal models of renal injury recapitulate events that are similar to humans, genetically engineered mouse models offer an important tool to delineate molecular mechanisms of renal diseases. A prevailing idea is that a number of these conditions are caused by aberrant function of genes that are also important in early kidney formation. Because absence of these genes from the beginning of kidney development often results in renal or other abnormalities and lethality, there is scarcity of animal models to examine the role of these genes in kidney disease in adulthood. Glial cell line-derived neurotrophic factor (GDNF), its coreceptor Gfra1 and receptor Ret constitute a signaling system that is critical for kidney development. It also regulates function of several tissue specific progenitors and is implicated in repair, regeneration and therapy of a number of conditions. However, biological roles of this signaling system in the postnatal kidney in normal and abnormal conditions are not known since its absence results in renal agenesis and lethality. We hypothesize that GDNF-Gfra1-Ret signaling is required for kidney maintenance in adult mice, it is important in kidney protection and regeneration after acute kidney injury (AKI), and GDNF can protect kidneys from AKI due to different types of insults by acting through Gfra1-Ret pathway. We have generated a number of animal models that are necessary to test these hypotheses. For example, to overcome lethality we have developed unique mouse models that will inactivate Gfra1 or Ret signaling after initial kidney development (conditional mice). To identify Gfra1 or Ret expressing cells in normal and disease states, we have generated "reporter" mice. To determine therapeutic potential of GDNF, we have established systemic delivery method that has shown protection in ischemic-reperfusion injury to the brain. The objective of specific Aim 1 in this proposal will be to use GDNF, Gfra1 and Ret reporter mice to identify where these proteins are expressed in the normal postnatal kidney and how their expression changes during AKI particularly in relation to repair and regeneration. In Specific Aim 2 we will use Gfra1 and Ret conditional mice to determine the impact of their loss on normal renal function in adult mice, and in AKI. In Aim 3, we will determine if exogenous treatment with GFLs in different AKI models is renoprotective, stimulates regeneration and occurs through Gfra1. Through these studies we will determine the importance of this pathway in renal health and disease. The insights gleaned will be of interest to a broad group of basic scientist, clinicians and patients affected by renal diseases. PUBLIC HEALTH RELEVANCE: GDNF-Gfra1-Ret signaling pathway is critical for kidney development and regulates function of a number of tissue specific stem cells. In this proposal we will utilize novel animal models to modulate this pathway and determine its role in the function of postnatal kidney in normal and disease states and examine if treatment with GDNF can protect kidneys from renal failure. The studies will provide novel insights into mechanisms of repair and regeneration and therapy in injured kidneys.
描述(由申请人提供):先天性、慢性和急性肾脏疾病对我们的社会造成了重大的发病率、死亡率和经济负担。通过确定导致肾脏疾病的发病机制,将对所有这些领域产生重大影响。由于人类和小鼠在肾脏发育和功能方面有许多共同的特征,并且肾脏损伤的动物模型也与人类相似,因此基因工程小鼠模型为描述肾脏疾病的分子机制提供了重要的工具。一种流行的观点是,许多这些情况是由基因的异常功能引起的,这些基因在早期肾脏形成中也很重要。由于从肾脏发育开始缺乏这些基因往往会导致肾脏或其他异常和致命,因此缺乏动物模型来研究这些基因在成年期肾脏疾病中的作用。胶质细胞系来源的神经营养因子(GDNF)及其辅助受体Gfra1和受体Ret构成了一个对肾脏发育至关重要的信号系统。它还调节几种组织特异性祖细胞的功能,并与许多疾病的修复、再生和治疗有关。然而,这个信号系统在正常和异常情况下在出生后肾脏中的生物学作用尚不清楚,因为它的缺失会导致肾脏发育不全和死亡。我们假设GDNF-Gfra1-Ret信号是成年小鼠肾脏维持所必需的,它在急性肾损伤(AKI)后的肾脏保护和再生中起重要作用,并且GDNF可以通过Gfra1-Ret途径保护肾脏免受不同类型损伤的AKI。我们已经建立了一些动物模型来检验这些假设。例如,为了克服致死率,我们开发了独特的小鼠模型,在初始肾脏发育后(条件小鼠)使Gfra1或Ret信号失活。为了鉴定正常和疾病状态下表达Gfra1或Ret的细胞,我们产生了“报告”小鼠。为了确定GDNF的治疗潜力,我们建立了在脑缺血再灌注损伤中显示保护作用的全身给药方法。本研究的目标是使用GDNF、Gfra1和Ret报告小鼠来确定这些蛋白在正常出生后肾脏中的表达位置,以及它们在AKI期间的表达变化,特别是与修复和再生有关。在Specific Aim 2中,我们将使用Gfra1和Ret条件小鼠来确定它们的丢失对成年小鼠和AKI正常肾功能的影响。在Aim 3中,我们将确定不同AKI模型中外源性gfl治疗是否具有肾保护作用,刺激再生并通过Gfra1发生。通过这些研究,我们将确定这一途径在肾脏健康和疾病中的重要性。收集到的见解将对基础科学家,临床医生和肾脏疾病患者的广泛群体感兴趣。公共卫生相关性:GDNF-Gfra1-Ret信号通路对肾脏发育至关重要,并调节许多组织特异性干细胞的功能。在本提案中,我们将利用新的动物模型来调节这一途径,并确定其在正常和疾病状态下出生后肾脏功能中的作用,并检查GDNF治疗是否可以保护肾脏免于肾功能衰竭。这些研究将为损伤肾脏的修复、再生和治疗机制提供新的见解。

项目成果

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Sanjay Jain其他文献

Sanjay Jain的其他文献

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{{ truncateString('Sanjay Jain', 18)}}的其他基金

A Computational IMage Analysis Platform (CIMAP) for HuBMAP
HuBMAP 的计算图像分析平台 (CIMAP)
  • 批准号:
    10841858
  • 财政年份:
    2023
  • 资助金额:
    $ 25.18万
  • 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
  • 批准号:
    10531101
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
  • 批准号:
    10867926
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
National Institute of Diabetes and Digestive and Kidney Diseases ATLAS (D2K-ATLAS) Center as an accessible, comprehensive data portfolio for renal and genitourinary development and disease
国家糖尿病、消化和肾脏疾病研究所 ATLAS (D2K-ATLAS) 中心作为肾脏和泌尿生殖发育和疾病的可访问、全面的数据组合
  • 批准号:
    10910532
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10530268
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
  • 批准号:
    10531099
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Kidney single cell and spatial molecular atlas project - KIDSSMAP
肾脏单细胞和空间分子图谱项目 - KIDSSMAP
  • 批准号:
    10705737
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10707948
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
National Institute of Diabetes and Digestive and Kidney Diseases ATLAS (D2K-ATLAS) Center as an accessible, comprehensive data portfolio for renal and genitourinary development and disease
国家糖尿病、消化和肾脏疾病研究所 ATLAS (D2K-ATLAS) 中心作为肾脏和泌尿生殖发育和疾病的可访问、全面的数据组合
  • 批准号:
    10605033
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:
Research Project 1: A Multidimensional Molecular Atlas of Healthy and Diseased Human Pediatric Kidney
研究项目 1:健康和患病人类儿童肾脏的多维分子图谱
  • 批准号:
    10530270
  • 财政年份:
    2022
  • 资助金额:
    $ 25.18万
  • 项目类别:

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  • 批准号:
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  • 财政年份:
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  • 财政年份:
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  • 项目类别:
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