Identification of Kidney Regeneration Mechanisms Using the Zebrafish

描述（由申请人提供） 翻译后摘要：肾脏疾病发生在世界范围内流行的比例。肾脏疾病病理学中常见的是构成肾单位的细胞的破坏，肾单位是肾脏器官的基本结构和功能单位。有趣的是，人类肾单位有能力通过再生取代受损的肾单位细胞。然而，这一观察结果与急性和慢性肾脏疾病的发病率不断增加不一致：虽然肾单位表现出再生能力，但这种特性存在惊人的未知限制。目前，负责驱动肾单位再生的机制是一个谜。肾脏疾病患者在等待器官移植时被迫接受透析治疗，通常要等几年才能获得器官，随着肥胖相关糖尿病的增加和人类寿命的延长，肾脏疾病的发病率不断上升，情况变得更加可怕。发现替代肾脏疾病治疗的一种创新方法是发现可以使用患者现有的肾细胞作为再生源来指导肾单位再生的分子信号。我已经创建了一个原始的斑马鱼肾单位再生模型，并建议在我的实验室中使用这个斑马鱼模型来揭示指导肾单位再生的机制。我以前证明了斑马鱼和人类的肾单位是相似的，这表明肾单位再生的机制可能是保守的。我们将利用斑马鱼的属性来发现可以调节脊椎动物肾单位再生的途径，利用在真实的时间内可视化和记录细胞事件的能力，并使用转基因、基因敲低和错误表达工具以高分辨率干扰分子事件。我们的斑马鱼肾再生模型提供了一个前所未有的新机会，以可视化肾单位细胞再生，并在整个脊椎动物的背景下进行实验研究。迄今为止，在现有的哺乳动物肾脏疾病或损伤模型中，肾单位再生的研究几乎不可能在分子遗传学水平上解决。拟开展的研究将（1）描述参与肾单位再生的细胞和分子事件，（2）阐明能够诱导、增强或抑制再生的信号通路。我们的发现将描绘一个肾单位再生的范例，可能导致新的治疗方法，使各种疾病状态下的肾功能恢复。 公共卫生相关性：肾脏的疾病是普遍的，并造成损害肾单位，功能单位，清洁身体的废物和调节水的平衡。肾单位损伤不能用目前的药物治疗恢复。拟议的研究将确定肾单位细胞如何在损伤后再生，了解这一过程有可能指导肾脏疾病新疗法的产生。

DESCRIPTION (Provided by the applicant) Abstract: Kidney diseases occur at epidemic proportions worldwide. Common among kidney disease pathology is the destruction of cells that comprise the nephron, the basic structural and functional unit of the kidney organ. Interestingly, human nephrons have the capacity to replace damaged nephron cells through regeneration. However, this observation is at odds with the growing incidence of acute and chronic kidney diseases: while nephrons exhibit regenerative capacity, there are striking, unknown limits to this property. Currently, the mechanisms that are responsible for driving nephron regeneration are a mystery. Patients with kidney disease are compelled to undergo dialysis regimens while awaiting organ transplant, often waiting several years before an organ is available, and the situation is steadily becoming more dire as kidney disease rates elevate in tandem with the rise in obesity-related diabetes and extensions in human lifespan. An innovative approach to discovering alternative kidney disease treatments is to discover the molecular signals that can instruct nephron regeneration using a patient's existing kidney cells as the regeneration source. I have created an original model of nephron regeneration in zebrafish, and propose to use this zebrafish model in my laboratory to uncover the mechanisms that direct nephron regeneration. I previously demonstrated that nephrons are similar in zebrafish and humans, suggesting that mechanisms of nephron regeneration are likely to be conserved. We will utilize the attributes of the zebrafish to discover the pathways that can modulate nephron regeneration in vertebrates, taking advantage of the ability to visualize and record cellular events in real time and perturb molecular events with high resolution using transgenics, gene knockdown and mis-expression tools. Our zebrafish kidney regeneration model provides an unprecedented, new opportunity to visualize nephron cell regeneration and conduct experimental studies in the context of a whole vertebrate animal. To date, the study of nephron regeneration has been virtually impossible to address at the level of molecular genetics with existint mammalian kidney disease or injury models. The proposed studies will (1) delineate the cellular and molecular events involved in nephron regeneration, and (2) elucidate the signaling pathways that are able to induce, enhance, or obviate regeneration. Our findings will delineate a paradigm of nephron regeneration that may lead to novel therapeutics that enable the restoration of kidney function in various disease states. Public Health Relevance: Diseases of the kidney are widespread and cause damage to nephrons, the functional units that cleanse the body of waste and regulate water balance. Nephron damage cannot be restored with current medical treatments. The proposed studies will determine how nephron cells can be regenerated following damage, and understanding this process has the potential to guide generation of novel therapies for kidney disease.