Origin and Regulation of Kidney Progenitor Cells

在脊椎动物器官发生过程中，一个重要的和反复出现的主题是单个细胞的早期特化。 或小区的小群组（即，祖细胞），在发育后期，产生特定的器官系统。为 例如，卵黄囊细胞的一个亚群是胚胎造血细胞和特异性神经细胞的第一来源。 嵴谱系产生外周神经系统的重要部分。然而，几乎没有数据表明， 脊椎动物肾脏最早的细胞肾脏的鉴定和表征 祖细胞是重要的，因为脊椎动物的肾脏是可再生的，但祖细胞的分子机制， 肾再生在很大程度上是未知的。成年肾脏的再生细胞可能是 胚胎中最早的肾祖细胞与发育有关。 这项建议旨在确定最早的胚胎细胞，产生脊椎动物肾脏（目的 1)并确定Lim 1和Pax 8在肾脏发育过程中的作用（目的2）。我们将检验这个假设 Lim 1和Pax 8是中间中胚层向肾限制组织发展的调节因子。 此外，我们将确定化合物4-（苯硫基）丁酸在影响 不仅在斑马鱼胚胎中，而且在器官培养中，肾组织特化（Aim 3）。我们使用 斑马鱼和非洲爪蟾胚胎，因为它们的遗传和胚胎学特征互补 以及哺乳动物模型的模型，以允许对小鼠早期肾脏发育进行实验研究 脊椎动物系统该提案中概述的目标联合收割机将实验胚胎学、分子生物学 和最先进的显微镜来鉴定肾祖细胞这些调查的结果直接 可转化为其他脊椎动物的努力，特别是人类描绘分子事件， 影响肾限制祖细胞分化。 这项研究与公共卫生的相关性是脊椎动物的肾脏是一个复杂的稳态 一种器官，其功能是给血液解毒，维持离子和水的平衡，并调节激素的释放。 肾脏形成或功能异常的生理后果往往是致命的， 器官移植是肾脏疾病唯一的长期治疗方法。未来的战略，以打击肾脏 疾病必须依赖于对导致疾病形成的最早期事件的基本理解。 肾

An essential and recurring theme during vertebrate organogenesis is the early specification of single or small groups of cells (i.e., progenitors) that, later in development, give rise to specific organ systems. For example, a subset of yolk sac cells is the first source of embryonic hematopoietic cells and specific neural crest lineages give rise to significant portions of the peripheral nervous system. Little data exist, though, on the earliest cells that give rise to the vertebrate kidney. Identification and characterization of kidney progenitor cells is important because the vertebrate kidney is regenerative, but the molecular mechanisms of nephric regeneration are largely unknown. It is possible that regenerative cells of the adult kidney are developmental^ related to the earliest kidney progenitor cells in the embryo. This proposal aims to identify the earliest embryonic cells that give rise to the vertebrate kidney(Aim 1) and determine the role of Lim1and Pax8 during kidney development (Aim 2). We will test the hypothesis that Lim1 and Pax8 are regulators of intermediate mesoderm progression to nephric restricted tissue. Moreover, we will determine the role the chemical compound, 4-(phenylthio)butyric acid plays in influencing nephric tissue specification not only in zebrafish embryos but also in organ culture (Aim 3). We use both zebrafish and Xenopus embryos because their genetic and embryological features complement each other and those of mammalian models to permit experimental investigation of early kidney development in a vertebrate system. The Aims outlined in this proposal combine experimental embryology, molecular biology, and state-of-the-art microscopy to identify kidney progenitor cells. Results of these investigations are directly translatable to efforts in other vertebrates, particularly humans for delineating molecular events that can influence kidney-restricted progenitor cell differentiation. The relevance of this research to public health is the vertebrate kidney is a complex homeostatic organ that functions to detoxify blood, maintain ion and water equilibrium, and regulate hormone release. The physiological consequences of abnormal kidney formation or function are frequently fatal, with dialysis and organ transplantation the only long-term treatments for kidney disease. Future strategies to fight kidney disease must rely on a fundamental understanding of the earliest events that lead to the formation of the kidney.