Podocyte depletion/ regeneration in evolution & reversal of diabetic nephropathy

进化中的足细胞耗竭/再生

基本信息

  • 批准号:
    8108290
  • 负责人:
  • 金额:
    $ 48.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-15 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Diabetic Nephropathy (DN) is the largest single cause of end-stage renal disease in the United States. Current therapies for diabetes are not effective in reversing established complications such as DN. We have recently reported a new murine model of DN, the BTBR mouse strain with the ob/ob leptin deficiency mutation that closely resembles human DN including early loss of podocytes (podo). We present preliminary data clearly demonstrating that reversibility of nephropathy can be achieved in our model. In this proposal, we build upon these observations to define and optimize strategies for reversal of DN with a focus on two fundamental mechanisms that may be pivotal in the pathogenesis of DN and its reversal: depletion of podos and their regeneration. We show in our model exciting data that podocyte number can be restored with reversal of DN. In our first specific aim, we develop a strategy to identify the source of the regenerating podos. Using lineage tracing studies, we will test whether neighboring parietal epithelial cells PECs can serve as a local progenitor cell niche for regenerating podos. We will test several interventions including commonly used therapies for human DN to test whether their lack of efficacy for reversal of DN is linked with their inability to promote restoration of podo #. We will extend our observations to human kidney biopsies of DN to directly translate our observations in mice to the human disease. In our second specific aim, we will investigate mechanisms that potentiate podo loss and those that facilitate regeneration, focusing on injury induced by mitochondrial oxidative stress induced by reactive oxygen species (mtROS), considered a principal cause of podocyte injury in DN. We utilize strategies of podocyte specific and systemic scavenging of mtROS to test whether these approaches can abrogate progression of DN and/or promote its reversal in conjunction with restoration of podo #. We pursue these strategies both by creation of transgenic mice that inducibly overexpress the ROS scavenger catalase in a mitochondrially restricted fashion, as well as by administration of novel peptides characterized by their ability to reduce mitochondrial oxidative stress. In aggregate, the proposed studies will enable testing of our central hypothesis: loss of podos is an early and proximate step in the development of the characteristic lesions of DN, that further podo loss and renewal are concurrently active processes, that prevention of podo loss substantially limits the development of DN, and ultimately that repair of DN requires restoration of podo number. The impact of these studies will be 1) to establish new paradigms that podo regeneration in DN can be achieved, and that place a new emphasis on PECs in the evolution and repair of DN. 2) to establish for the first time a mechanism by which podo regeneration is accomplished and by which reversal of DN may be achieved, by employing highly specific tests of whether mtROS injuries to podos are causal and required for the development of DN. 3) If successful, restoration of podo loss by a novel small molecule inhibitor of mtROS could serve as a proof of principle for a new class of therapeutic agents with potential to reverse human DN. PUBLIC HEALTH RELEVANCE: These studies use a new mouse model of diabetic kidney disease characterized by our laboratory (the BTBR mouse strain with leptin deficiency) that is reversible when leptin is replaced. This grant explores mechanisms underlying reversibility (replacement of kidney cell populations that are typically lost in human and experimental diabetic kidney disease) with emphasis on the podocyte, a unique cell type in the kidney. We then will test new therapies, based on correcting metabolic injuries to mitochondria (an organelle present within all cells), that are specifically directed to podocyte mitochondria, as a way to promote reversal of diabetic kidney disease.
描述(由申请人提供):糖尿病肾病(DN)是美国终末期肾病的最大单一原因。目前的糖尿病疗法在逆转已确定的并发症如DN方面无效。我们最近报道了一种新的DN小鼠模型,即具有ob/ob瘦素缺乏突变的BTBR小鼠品系,其与人类DN非常相似,包括足细胞的早期损失(podo)。我们目前的初步数据清楚地表明,在我们的模型中可以实现可逆性肾病。在这个建议中,我们建立在这些观察,以确定和优化的战略,逆转DN的重点是两个基本机制,可能是关键的发病机制,DN和其逆转:消耗足细胞和再生。我们在我们的模型中显示了令人兴奋的数据,足细胞数量可以通过逆转DN来恢复。在我们的第一个具体目标中,我们开发了一种策略来识别再生Podos的来源。使用谱系追踪研究,我们将测试相邻的壁上皮细胞佩奇是否可以作为再生足的局部祖细胞龛。我们将测试几种干预措施,包括人类DN的常用疗法,以测试其逆转DN的疗效缺乏是否与其不能促进足修复有关。我们将把我们的观察扩展到DN的人肾活检,以直接将我们在小鼠中的观察转化为人类疾病。在我们的第二个具体目标中,我们将研究增强足细胞损失和促进再生的机制,重点关注由活性氧(mtROS)诱导的线粒体氧化应激诱导的损伤,这被认为是DN足细胞损伤的主要原因。我们利用足细胞特异性和全身性清除线粒体ROS的策略来测试这些方法是否可以消除DN的进展和/或促进其逆转与足细胞的恢复。我们追求这些策略,既通过创建转基因小鼠,诱导过表达的ROS清除剂过氧化氢酶在一个限制性的方式,以及通过管理的新的肽,其特征在于它们的能力,以减少线粒体氧化应激。总的来说,拟议的研究将使我们的中心假设的测试:足的损失是一个早期和接近的步骤,在DN的特征性病变的发展,进一步的足的损失和更新是同时活跃的过程,预防足的损失大大限制了DN的发展,并最终修复DN需要恢复足的数量。这些研究的影响将是:1)建立新的范式,可以实现DN中的足再生,并将新的重点放在佩奇在DN的演变和修复中。2)通过采用高度特异性的测试来确定线粒体ROS对足细胞的损伤是否是糖尿病肾病发展的原因和必需条件,首次建立了足细胞再生的机制,并通过该机制可以实现糖尿病肾病的逆转。3)如果成功的话,通过一种新的mtROS小分子抑制剂恢复足缺失可以作为一类新的治疗剂的原理证明,这些治疗剂有可能逆转人DN。 公共卫生相关性:这些研究使用了一种新的糖尿病肾病小鼠模型,其特征在于我们的实验室(具有瘦素缺乏的BTBR小鼠品系),当瘦素被替代时,该模型是可逆的。这项资助旨在探索可逆性的潜在机制(替代人类和实验性糖尿病肾病中通常丢失的肾脏细胞群),重点是肾脏中独特的细胞类型-足细胞。然后,我们将测试基于纠正线粒体(所有细胞内存在的细胞器)代谢损伤的新疗法,这些疗法专门针对足细胞线粒体,作为促进糖尿病肾病逆转的一种方法。

项目成果

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CHARLES E ALPERS其他文献

CHARLES E ALPERS的其他文献

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{{ truncateString('CHARLES E ALPERS', 18)}}的其他基金

Podocyte depletion/ regeneration in evolution & reversal of diabetic nephropathy
进化中的足细胞耗竭/再生
  • 批准号:
    8547054
  • 财政年份:
    2011
  • 资助金额:
    $ 48.5万
  • 项目类别:
Podocyte depletion/ regeneration in evolution & reversal of diabetic nephropathy
进化中的足细胞耗竭/再生
  • 批准号:
    8332109
  • 财政年份:
    2011
  • 资助金额:
    $ 48.5万
  • 项目类别:
Podocyte depletion/ regeneration in evolution & reversal of diabetic nephropathy
进化中的足细胞耗竭/再生
  • 批准号:
    8730623
  • 财政年份:
    2011
  • 资助金额:
    $ 48.5万
  • 项目类别:
Core--Histology/ Immunohistochemistry/ In Situ Hybridization
核心--组织学/免疫组织化学/原位杂交
  • 批准号:
    7337076
  • 财政年份:
    2007
  • 资助金额:
    $ 48.5万
  • 项目类别:
PATHOPHYSIOLOGY OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS
冷球蛋白血症性肾小球肾炎的病理生理学
  • 批准号:
    7367057
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:
Core--Histology/Immunohistochemistry/In Situ Hybridizati
核心--组织学/免疫组织化学/原位杂交
  • 批准号:
    6774627
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:
PDGF-D INDUCED MODELS OF MESANGIAL GLOMERULOPATHY
PDGF-D 诱导的系膜肾小球病模型
  • 批准号:
    6951083
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:
PDGF-D INDUCED MODELS OF MESANGIAL GLOMERULOPATHY
PDGF-D 诱导的系膜肾小球病模型
  • 批准号:
    6863291
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:
PATHOPHYSIOLOGY OF CRYOGLOBULNEMIC GLOMERULONEPHRITIS
冷球蛋白性肾小球肾炎的病理生理学
  • 批准号:
    6895293
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:
PATHOPHYSIOLOGY OF CRYOGLOBULINEMIC GLOMERULONEPHRITIS
冷球蛋白血症性肾小球肾炎的病理生理学
  • 批准号:
    6741188
  • 财政年份:
    2004
  • 资助金额:
    $ 48.5万
  • 项目类别:

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