Novel Targets for the Treatment of Diabetic Kidney Disease

治疗糖尿病肾病的新靶点

基本信息

批准号：
9031226
负责人：
Robert Spurney
金额：
--
依托单位：
DURHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031226
关键词：
Adult Albuminuria Angiotensin II Animals Apoptosis Apoptosis Regulation Gene Apoptotic Applications Grants Attenuated Calcineurin Calcineurin inhibitor Calcium Cations Cell Nucleus Cells Characteristics Clinical Complication Cre-LoxP Cytoplasm Cytosol Dependence Diabetes Mellitus Diabetic Nephropathy Disease Disease Progression Economic Burden Economics End stage renal failure Environment Etiology FK506 Focal Segmental Glomerulosclerosis Gene Targeting Genetic Genetic Transcription Goals Healthcare Systems Human Hyperglycemia Hypertension In Vitro Incidence Injury Insulin-Dependent Diabetes Mellitus Ion Channel Kidney Kidney Failure Knock-out Mediating Mediator of activation protein Medical Economics Messenger RNA Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Export Nuclear Import Pathogenesis Patients Peptides Phosphotransferases Play Population Preparation Prevalence Protein Isoforms Proteinuria Renal glomerular disease Renin-Angiotensin System Rodent Role Signal Pathway Signal Transduction System T-Cell Activation Technology United States Up-Regulation Veterans base calcineurin phosphatase diabetic drug development gain of function mutation glomerulosclerosis in vivo interest mouse model new therapeutic target non-diabetic novel novel strategies nuclear factors of activated T-cells podocyte public health relevance receptor research study therapeutic target transcription factor treatment strategy type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the most common cause of end stage kidney disease (ESKD) in the United States. As a result, much effort has been devoted to understanding the mechanisms that promote glomerular damage in diabetic kidney disease. A large body of evidence suggests that glomerular podocytes play a pivotal role in the pathogenesis of DN. A reduced number of podocytes is a characteristic feature of both animals and humans with diabetic kidney disease. Because podocytes are terminally differentiated cells with little potential for proliferation, podocytes that are lost cannot be effectively replaced causing instability of glomerular tuft and promoting disease progression. While the etiology of podocyte loss is likely multifactorial, apoptosis is a prominent feature of diabetic kidney disease and is an important cause of podocyte loss in DN. A key regulator of apoptosis is intracellular calcium. Indeed, a large number of signaling pathways implicated in the pathogenesis of diabetic kidney disease increase intracellular calcium levels. Enhanced intracellular calcium levels activate downstream signaling pathways including the calcium activated phosphatase calcineurin (CN). Our lab has found that receptor systems that increase cytosolic calcium levels and stimulate CN activity promote podocyte apoptosis by mechanisms that are mediated by CN-dependent activation of NFAT (nuclear factor of activated T cells). An important gene target of CN signaling is the transient receptor potential cation channel C6 (TRPC6). These observations appear relevant to DN because: 1. TRPC6 is upregulated in a mouse model of type 1 diabetes (Akita mice), 2. The CN inhibitor FK506 attenuates podocyte apoptosis in Akita mice, and 3. Albuminuria is reduced in Akita mice lacking TRPC6. Based on these observations, we hypothesized that CN plays a key role in DN through mechanisms that involve up-regulation of TRPC6. To investigate this hypothesis, 3 specific aims are proposed. In specific aim #1, we will investigate the dynamic shuttling of NFAT isoforms between the cytosol and nucleus in cultured podocytes, which is dependent on the relative activity of CN phosphatases and NFAT kinases. The goal of these studies is to identify novel strategies for modulating CN- NFAT signaling in glomerular diseases. In specific aim #2, we will determine if the absence of TRPC6 inhibits podocyte apoptosis and reduces glomerular injury in Akita mice lacking TRPC6. In specific aim #3, we will determine if podocyte specific deletion of CN decreases podocyte apoptosis in DN and, in turn, ameliorates kidney injury in Akita mice. The long-term goal of the proposed studies is to identify novel therapeutic targets for the treatment of DN in humans.

描述（由申请人提供）：糖尿病肾病 (DN) 是美国终末期肾病 (ESKD) 的最常见原因，因此，人们投入了大量精力来了解糖尿病肾病中促进肾小球损伤的机制。表明肾小球足细胞在 DN 的发病机制中发挥着关键作用，足细胞数量减少是患有糖尿病肾病的动物和人类的一个特征，因为足细胞是终末分化的细胞。由于足细胞的增殖潜力很小，丢失的足细胞不能有效地引起肾小球簇的替代不稳定并促进疾病进展。虽然足细胞丢失的病因可能是多因素的，但细胞凋亡是糖尿病肾病的一个突出特征，也是足细胞发生的一个重要原因。事实上，与糖尿病肾病发病机制有关的大量信号通路会增加细胞内钙水平，从而激活下游细胞凋亡。我们的实验室发现，增加胞浆钙水平并刺激 CN 活性的受体系统通过 CN 依赖性 NFAT（激活 T 细胞的核因子）激活介导的机制促进足细胞凋亡。 CN 信号传导的一个重要基因靶标是瞬时受体电位阳离子通道 C6 (TRPC6)。这些观察结果似乎与 DN 相关，因为： 1. TRPC6 在 1 型小鼠模型中表达上调。 1. 糖尿病（秋田小鼠），2. CN 抑制剂 FK506 减弱秋田小鼠的足细胞凋亡，3. 缺乏 TRPC6 的秋田小鼠的蛋白尿减少。基于这些观察，我们探索了 CN 通过以下机制在 DN 中发挥关键作用。为了研究这一假设，我们提出了 3 个具体目标，在具体目标 1 中，我们将研究 NFAT 的动态穿梭。培养的足细胞中细胞质和细胞核之间的亚型，这取决于 CN 磷酸酶和 NFAT 激酶的相对活性。这些研究的目标是确定在肾小球疾病中调节 CN-NFAT 信号传导的新策略。我们将确定缺乏 TRPC6 是否会抑制缺乏 TRPC6 的秋田小鼠的足细胞凋亡并减少肾小球损伤。在具体目标#3 中，我们将确定足细胞是否会抑制足细胞凋亡。 CN 的特异性缺失可减少 DN 中的足细胞凋亡，进而改善秋田小鼠的肾损伤。拟议研究的长期目标是确定治疗人类 DN 的新治疗靶点。