Terminal Differentiation of the Renal Epithelium

肾上皮的终末分化

• 批准号: 8072173
• 负责人: Samir S El-Dahr
• 金额: $ 27.93万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072173
• 关键词: Accounting; Acetylation; Acute Renal Failure with Renal Papillary Necrosis; Address; Apoptosis; Binding; Biochemical; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Child; Chronic Kidney Failure; Clinical; Congenital Abnormality; Defect; Development; Dialysis procedure; Differentiation and Growth; Disease; Dysplasia; Epithelial; Epithelial Cells; Equilibrium; Event; Exhibits; Failure; Family; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Grant; Growth and Development function; Health; Homologous Gene; Infant; Investigation; Kidney; Knock-in Mouse; Lysine; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mesenchymal; Metanephric Diverticulum; Modeling; Molecular; Mus; Mutation; N-terminal; Nephrons; Organ Culture Techniques; Organogenesis; Pathway interactions; Pattern; Phenotype; Phosphorylation; Physiological; Play; Process; Protein Isoforms; Protein p53; Recovery; Role; Serine; Signal Transduction; Stem cells; Stress; System; Testing; Transgenic Mice; Transplantation; Tumor Suppressor Proteins; Ubiquitination; Ureter; base; cell growth; clinically significant; gain of function; gene repression; in vivo; insight; kidney cell; kidney epithelial cell; malformation; member; multicatalytic endopeptidase complex; nephrogenesis; novel; prevent; programs; promoter; renal epithelium; response; senescence; spatiotemporal; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The molecular basis of terminal nephron differentiation, the process by which immature renal epithelial cells exit the cell cycle and express physiological functions, remains obscure. Failure of terminal nephron differentiation results in renal dysplasia, cystogenesis and cancer. Thus, a better understanding of the transcriptional framework which regulates renal cell differentiation is of great clinical significance. The tumor suppressor protein, p53, is a member of a family of transcription factors that regulate cellular growth, differentiation, senescence and apoptosis, and play a key role in cell fate determination during development and in response to stress. During the previous funding period, we demonstrated that p53 and its homologue p73 act as master transcriptional regulators upstream of genes required for terminal nephron differentiation; this function of p53/p73 is accomplished via cooperation with other developmentally regulated transcription factors and recruitment of co-activators or co-repressors. Consistent with this role, p53 -/- mice exhibit defects in terminal nephron differentiation, which can be reproduced by kidney-specific deletion/inactivation of p53. The overall goal of this competing grant renewal is to elucidate the mechanisms governing p53 activation and commitment to promote the terminal differentiation fate in the developing kidney. We will use a variety of in vivo genetic and biochemical approaches, together with an in vitro organ culture system, to test a model in which Mdm2 and other negative regulators of p53 exert strict spatiotemporal control on p53 during terminal nephron differentiation. We propose that p53 is preferentially required to execute a differentiation program in the ureteric bud cell lineage, and that this function is orchestrated and deciphered by distinct acetylation and phosphorylation cassettes which differentially influence gene expression patterns and thus cell fate. Investigations of how p53 is regulated during development and how p53 executes its differentiation functions are important basic steps toward understanding the genetic control of organogenesis. The proposed studies have important clinical implications as abnormal renal development is the leading cause of chronic renal failure in infants and children. PUBLIC HEALTH RELEVANCE: This proposal addresses a critical step in kidney development related to the cellular and molecular events that control the transition of immature kidney cells to become differentiated and functional. Abnormalities of kidney development (i.e., congenital malformations) account for up to 40% of cases of chronic kidney failure in infants and children requiring dialysis and transplantation. Understanding how kidney epithelial cells transition from an immature to a more differentiated fate should provide insights into novel treatments of important diseases including kidney malformations, cancer, and recovery from acute kidney injury.

描述（由申请人提供）：终末肾单位分化（未成熟肾上皮细胞退出细胞周期并表达生理功能的过程）的分子基础仍然不清楚。终末肾单位分化失败导致肾发育不良、囊肿发生和癌症。因此，更好地了解调节肾细胞分化的转录框架具有重要的临床意义。肿瘤抑制蛋白 p53 是转录因子家族的成员，可调节细胞生长、分化、衰老和凋亡，并在发育和应激反应过程中的细胞命运决定中发挥关键作用。在之前的资助期间，我们证明了p53及其同源物p73作为终末肾单位分化所需基因上游的主转录调节因子； p53/p73 的这一功能是通过与其他发育调节转录因子的合作以及共激活子或共抑制子的募集来实现的。与这一作用一致，p53 -/- 小鼠表现出终末肾单位分化缺陷，这种缺陷可以通过肾脏特异性删除/失活 p53 来重现。这项竞争性拨款更新的总体目标是阐明控制 p53 激活的机制以及促进发育中肾脏终末分化命运的承诺。我们将使用多种体内遗传和生化方法，以及体外器官培养系统，来测试Mdm2和p53的其他负调节因子在终末肾单位分化过程中对p53进行严格时空控制的模型。我们认为p53是输尿管芽细胞谱系中执行分化程序所必需的，并且该功能是由不同的乙酰化和磷酸化盒精心策划和破译的，这些盒不同地影响基因表达模式，从而影响细胞命运。研究 p53 在发育过程中如何受到调节以及 p53 如何执行其分化功能是了解器官发生的遗传控制的重要基本步骤。拟议的研究具有重要的临床意义，因为肾脏发育异常是婴儿和儿童慢性肾衰竭的主要原因。公共健康相关性：该提案解决了肾脏发育中与控制未成熟肾细胞向分化和功能转变的细胞和分子事件相关的关键步骤。在需要透析和移植的婴儿和儿童慢性肾衰竭病例中，肾脏发育异常（即先天畸形）占高达 40%。了解肾上皮细胞如何从不成熟的状态转变为更加分化的命运，应该可以为重要疾病的新疗法提供见解，包括肾脏畸形、癌症和急性肾损伤的恢复。