Origin and Regulation of Kidney Progenitor Cells

脊椎动物器官发生过程中一个基本且反复出现的主题是单个 或一小群细胞(即祖细胞)，在后来的发育过程中，形成特定的器官系统。为 例如，卵黄囊细胞亚群是胚胎造血细胞和特定神经细胞的第一来源。 脊谱系形成了周围神经系统的重要部分。然而，几乎没有数据存在于 形成脊椎动物肾脏的最早的细胞。肾脏的鉴定与鉴定 祖细胞很重要，因为脊椎动物的肾脏是可以再生的，但 肾再生在很大程度上是未知的。成人肾脏的再生细胞有可能是 发育与胚胎中最早的肾祖细胞有关。 这项提议旨在鉴定形成脊椎动物肾脏的最早的胚胎细胞(AIM 1)并确定Lim1和Pax8在肾脏发育中的作用(目标2)。我们将检验这一假设 LIM1和Pax8是中胚层向肾脏受限组织发展的中间调节因子。 此外，我们将确定化合物4-(苯硫基)丁酸在影响 肾脏组织规格不仅在斑马鱼胚胎中，而且在器官培养中也是如此(目标3)。我们两个都用 斑马鱼和非洲爪哇胚胎，因为它们的遗传和胚胎学特征相辅相成 和哺乳动物模型，以允许对早期肾脏发育的实验研究 脊椎动物系统。这项提案概述的目标结合了实验胚胎学、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 可翻译为其他脊椎动物，特别是人类的努力，以描述可以 影响肾功能受限的祖细胞分化。 这项研究与公共健康的相关性在于，脊椎动物的肾脏是一种复杂的动态平衡 血液解毒、维持离子和水平衡、调节激素释放的器官。 通过透析，肾脏形成或功能异常的生理后果往往是致命的。 而器官移植是肾脏疾病的唯一长期治疗方法。对抗肾脏的未来战略 疾病必须依赖于对导致疾病形成的最早事件的基本了解 肾脏。

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.