Origin and Regulation of Kidney Progenitor Cells

肾祖细胞的起源和调控

• 批准号: 7193473
• 负责人: Neil A Hukriede
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193473
• 关键词: Address; Adult; Arts; Blood; Butyric Acid; Butyric Acids; Cell Differentiation process; Cell Lineage; Cell Transplantation; Cells; Chemicals; Commit; Complement; Complex; Data; Development; Dialysis procedure; Embryo; Embryology; Equilibrium; Event; Future; Gastrula; Genes; Genetic; Genetic Screening; Goals; Hematopoietic; Hormones; Human; Intermediate Mesoderm; Investigation; Ions; Kidney; Kidney Diseases; Lead; Maps; Mesenchyme; Mesoderm Cell; Microscopy; Modeling; Molecular; Molecular Biology; Natural regeneration; Neural Crest; Organ; Organ Culture Techniques; Organ Transplantation; Organogenesis; Peripheral Nervous System; Pharmaceutical Preparations; Physical Dialysis; Physiological; Play; Primordium; Public Health; Regulation; Reporter; Research; Research Personnel; Role; Source; Specific qualifier value; Staging; Stem cells; Structure; System; Testing; Time; Tissues; Transgenic Organisms; Vertebrates; Water; Xenopus; Xenopus laevis; Yolk Sac; Zebrafish; base; blastomere structure; body system; fighting; insight; kidney cell; kidney hypertrophy; nephrogenesis; progenitor; programs; research study; small molecule; small molecule libraries; transcription factor

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.

描述（由申请人提供）：脊椎动物器官发生过程中一个重要且反复出现的主题是单个或小群细胞（即祖细胞）的早期规范，这些细胞在发育后期产生特定的器官系统。例如，卵黄囊细胞的子集是胚胎造血细胞的第一来源，并且特定的神经嵴谱系产生周围神经系统的重要部分。然而，关于形成脊椎动物肾脏的最早细胞的数据却很少。肾脏祖细胞的鉴定和表征非常重要，因为脊椎动物肾脏是可再生的，但肾再生的分子机制在很大程度上尚不清楚。成体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。该提案旨在鉴定产生脊椎动物肾脏的最早胚胎细胞（目标 1），并确定 Lim1 和 Pax8 在肾脏发育过程中的作用（目标 2）。我们将检验 Lim1 和 Pax8 是中间中胚层进展到肾限制组织的调节因子的假设。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（目标 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与哺乳动物模型的遗传和胚胎学特征互补，从而可以对脊椎动物系统中的早期肾脏发育进行实验研究。该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脏祖细胞。这些研究的结果可直接转化为其他脊椎动物，特别是人类的努力，以描绘可以影响肾脏限制性祖细胞分化的分子事件。这项研究与公共健康的相关性在于，脊椎动物的肾脏是一个复杂的稳态器官，具有解毒血液、维持离子和水平衡以及调节激素释放的功能。肾脏形成或功能异常的生理后果往往是致命的，透析和器官移植是肾脏疾病的唯一长期治疗方法。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事件的基本了解。