Role of p53 in Kidney Development: Modeling Renal Anomalies of Li-Fraumeni Patients

p53 在肾脏发育中的作用：Li-Fraumeni 患者肾脏异常建模

基本信息

批准号：
9765314
负责人：
Rachel Katherine Miller
金额：
$ 11.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765314
关键词：
Affect Animal Model Area Benign Clustered Regularly Interspaced Short Palindromic Repeats Complement Cystic kidney Data Defect Development Doctor of Medicine Doctor of Philosophy Embryo Foundations Functional disorder Future General Population Genes Genetic Diseases Genetic Transcription Genitourinary system Germ-Line Mutation Glomerular Filtration Rate Goals High Prevalence Human Genetics Incidence Individual Kidney Kidney Neoplasms Knock-out Knockout Mice Lead Li-Fraumeni Syndrome Magnetic Resonance Imaging Malignant Neoplasms Modeling Molecular Molecular Analysis Mutation Nephrons Ovarian Cysts Pathology Patients Pattern Play Positioning Attribute Predisposition Prevalence Process Protocols documentation Regulation Renal agenesis Renal function Renal tubule structure Research Role Side Signal Transduction Structure Syndrome System TP53 gene Testing Time Tumor Suppressor Proteins Ureter WNT Signaling Pathway Xenopus base beta catenin early onset experimental study gain of function innovation insight kidney malformation knock-down lifetime risk model development nephrogenesis novel novel strategies planar cell polarity reproductive tract

项目摘要

PROJECT SUMMARY/ ABSTRACT Patients with Li-Fraumeni syndrome are predisposed to cancer resulting from germline mutations in the tumor suppressor, p53. Inheritance of mutations in p53 occurs in an autosomal dominant pattern and results in an increased lifetime risk for developing multiple malignancies with a significant likelihood of early onset. Although prior studies using mouse knockouts have demonstrated that p53 plays a role in kidney formation, developmental kidney anomalies have not been associated with p53 mutations seen in Li-Fraumeni patients. Preliminary MRI data indicate that these patients have a higher incidence of urogenital anomalies than the general population. Thus, the goal of this proposal is to utilize Xenopus embryos to assess p53's fundamental role in kidney development and to generate animal models to determine whether p53 mutations seen in Li- Fraumeni patients result in renal anomalies. The proposed experiments will test the hypothesis that the p53 dysfunction in Li-Fraumeni patients results in kidney developmental anomalies. The hypothesis will be tested through the following aims: Aim 1. Evaluate kidney defects resulting from p53 disruption in Xenopus embryos. Previous studies showed that p53-null mouse embryos have developmental kidney defects, including duplex ureter and renal hypoplasia. Preliminary data indicate that similar nephric developmental defects are also present when p53 levels are reduced in the kidneys of Xenopus embryos, a useful model for dissecting the mechanisms that contribute to developmental defects. To set the foundation for future analysis of the molecular mechanism of p53 activity, the hypothesis that p53 regulates nephron differentiation will be tested in the Xenopus kidney. This will be achieved through novel strategies targeting CRISPR knockout of p53 to the Xenopus kidney, quantitation of pronephric developmental features, and analysis of expression of markers of kidney development. Aim 2. Determine whether p53 mutations seen in Li-Fraumeni patients result in renal anomalies. Preliminary MRI data indicate that Li-Fraumeni patients have an increased incidence of urogenital anomalies. The hypothesis that the p53 mutations that cause Li-Fraumeni syndrome result in disruption of Xenopus nephron development will be tested, thereby generating animal models of Li-Fraumeni kidney anomalies for future research. Given that the p53 mutations from these patients are anticipated to act through gain-of-function mechanisms, this will be carried out by targeting expression of the p53 alterations to the Xenopus kidney, studies that would be difficult and time-prohibitive in other models. Overall, the experiments proposed in this application will facilitate our understanding of how p53 affects nephron formation generally and how Li-Fraumeni patient mutations in p53 may disrupt this process.

项目概要/摘要 Li-Fraumeni 综合征患者易患由肿瘤种系突变引起的癌症抑制器，p53。 p53 突变的遗传以常染色体显性模式发生，并导致一生中患多种恶性肿瘤的风险增加，并且很可能早发。虽然先前使用小鼠基因敲除的研究表明 p53 在肾脏形成中发挥作用， Li-Fraumeni 患者的肾脏发育异常与 p53 突变无关。初步 MRI 数据表明，这些患者的泌尿生殖系统异常发生率高于正常患者。一般人群。因此，该提案的目标是利用非洲爪蟾胚胎来评估 p53 的基本功能肾脏发育中的作用并生成动物模型以确定 p53 突变是否在 Li-中出现 Fraumeni 患者会导致肾脏异常。所提出的实验将检验 p53 的假设 Li-Fraumeni 患者的功能障碍会导致肾脏发育异常。假设将被检验通过以下目标：目标 1. 评估爪蟾胚胎中 p53 破坏导致的肾脏缺陷。先前的研究表明，p53缺失的小鼠胚胎具有发育性肾脏缺陷，包括双链体输尿管和肾发育不全。初步数据表明，类似的肾发育缺陷也存在于当非洲爪蟾胚胎肾脏中的 p53 水平降低时，就会出现这种现象，这是解剖导致发育缺陷的机制。为以后的分析奠定基础 p53 活性的分子机制，p53 调节肾单位分化的假设将在爪蟾肾。这将通过针对 p53 的 CRISPR 敲除的新策略来实现非洲爪蟾肾、前肾发育特征的定量以及前肾标记物表达分析肾脏发育。目标 2. 确定 Li-Fraumeni 患者中发现的 p53 突变是否会导致肾病异常。初步 MRI 数据表明 Li-Fraumeni 患者泌尿生殖系统疾病的发生率增加异常。导致 Li-Fraumeni 综合征的 p53 突变导致破坏将测试非洲爪蟾肾单位的发育，从而生成 Li-Fraumeni 肾的动物模型未来研究的异常情况。鉴于这些患者的 p53 突变预计将通过功能获得机制，这将通过靶向 p53 改变的表达来实现爪蟾肾，在其他模型中进行的研究将是困难且耗时的。总的来说，实验本申请中提出的建议将有助于我们了解 p53 一般如何影响肾单位的形成以及 Li-Fraumeni 患者 p53 突变如何破坏这一过程。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of Multicolor Fluorescent Probes for Heterogeneous Aβ Deposits in Alzheimer's Disease.

DOI：
10.3389/fnagi.2021.802614
发表时间：
2021
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Mukherjee A;Al-Lahham R;Corkins ME;Samanta S;Schmeichel AM;Singer W;Low PA;Govindaraju T;Soto C
通讯作者：
Soto C

Aquatic models of human ciliary diseases.