Origin and Regulation of Kidney Progenitor Cells

描述（由申请人提供）：在脊椎动物器官发生过程中，一个基本的和反复出现的主题是单个或小细胞群的早期特化（即，祖细胞），在发育后期，产生特定的器官系统。例如，卵黄囊细胞的亚群是胚胎造血细胞的第一来源，特定的神经嵴谱系产生外周神经系统的重要部分。然而，关于脊椎动物肾脏形成的最早细胞的数据很少。由于脊椎动物的肾脏是可再生的，所以对肾脏祖细胞的鉴定和表征是重要的，但是肾脏再生的分子机制在很大程度上是未知的。成年肾脏的再生细胞可能与胚胎中最早的肾脏祖细胞发育相关。该提案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）。我们将测试的假设，Lim 1和Pax 8的中间中胚层进展到肾脏限制组织的调节器。此外，我们将确定化合物4-（苯硫基）丁酸不仅在斑马鱼胚胎中而且在器官培养中影响肾组织规格的作用（目的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相互补充，哺乳动物模型，允许在脊椎动物系统的早期肾脏发育的实验研究。本提案中概述的目标结合了联合收割机实验胚胎学、分子生物学和最先进的显微镜技术来鉴定肾祖细胞。这些研究的结果可以直接转化为其他脊椎动物，特别是人类的努力，描绘分子事件，可以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肾脏是一个复杂的稳态器官，其功能是解毒血液，维持离子和水平衡，并调节激素释放。肾脏形成或功能异常的生理后果通常是致命的，透析和器官移植是肾脏疾病唯一的长期治疗方法。未来对抗肾脏疾病的策略必须依赖于对导致肾脏形成的最早期事件的基本理解。

DESCRIPTION (provided by applicant): 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 Lim1 and 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.