权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8730623
负责人：
CHARLES E ALPERS
金额：
$ 39.33万
依托单位：
UNIVERSITY OF WASHINGTON
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730623
关键词：
Accounting Advanced Development Animal Model BTBR Mouse Basement membrane Biological Preservation Biopsy Cell Line Cells Characteristics Chronic Clinical Data Development Diabetic Nephropathy Diabetic mouse End stage renal failure Epithelial Cells Evolution Goals Grant Human Infusion procedures Injury Intervention Kidney Kidney Diseases Kidney Failure Label Laboratories Leptin Leptin deficiency Lesion Link Metabolic Mitochondria Modeling Mouse Strains Mus Mutation NADPH Oxidase Natural regeneration Organelles Outcome Oxidative Stress Parietal Pathogenesis Pathologic Peptides Play Population Prevention Process Progressive Disease Reactive Oxygen Species Recruitment Activity Reporting Role Site Source Stem cells Testing Therapeutic Therapeutic Agents Time Transgenic Mice Translating Treatment Efficacy United States base catalase cell transformation cell type diabetes mellitus therapy human disease in vivo inhibitor/antagonist injured kidney cell mouse model novel overexpression podocyte prevent repaired restoration small molecule type I and type II diabetes

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.

描述（由申请人提供）：糖尿病肾病（DN）是美国终末期肾脏疾病的最大单一原因。目前的糖尿病治疗方法在逆转糖尿病肾病等已建立的并发症方面并不有效。我们最近报道了一种新的DN小鼠模型，具有ob/ob瘦素缺乏症突变的BTBR小鼠菌株，与人类DN非常相似，包括早期足细胞丢失（podo）。我们提供的初步数据清楚地表明，肾病的可逆性可以在我们的模型中实现。在本研究中，我们以这些观察结果为基础，定义并优化了DN的逆转策略，重点关注两个可能在DN发病机制及其逆转中起关键作用的基本机制：足细胞的消耗和它们的再生。我们在我们的模型中显示了令人兴奋的数据，足细胞数量可以随着DN的逆转而恢复。在我们的第一个具体目标中，我们制定了一项策略来确定再生足弓的来源。通过谱系追踪研究，我们将测试邻近的顶壁上皮细胞PECs是否可以作为局部祖细胞生态位用于足趾再生。我们将测试几种干预措施，包括人类DN常用的治疗方法，以测试它们对DN缺乏逆转功效是否与它们无法促进podo #的恢复有关。我们将把我们的观察扩展到DN的人类肾脏活检，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，我们将研究足细胞丢失和促进再生的机制，重点关注活性氧（mtROS）诱导的线粒体氧化应激诱导的损伤，这被认为是DN中足细胞损伤的主要原因。我们利用足细胞特异性和系统清除mtROS的策略来测试这些方法是否可以消除DN的进展和/或促进其逆转并恢复podo #。我们通过创造转基因小鼠，诱导过氧化氢酶以线粒体受限的方式过度表达ROS清除剂，以及通过施用以其减少线粒体氧化应激能力为特征的新型肽来实现这些策略。总的来说，提出的研究将能够验证我们的中心假设：足突的丢失是DN特征性病变发展的早期和近似步骤，进一步的足突丢失和更新是同时活跃的过程，防止足突丢失实质上限制了DN的发展，最终修复DN需要恢复足突数量。这些研究的影响将是1)建立新的范式，以实现DN的podo再生，并重新强调PECs在DN的进化和修复中的作用。2)首次建立足部再生和DN逆转的机制，通过高度特异性的试验来确定mtROS对足部的损伤是否有因果关系，以及是否为DN的发生所必需。3)如果成功，一种新的mtROS小分子抑制剂可以恢复podo的丧失，这可能为一种新的治疗药物提供原理证明，这种药物有可能逆转人类DN。