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

• 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
• 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

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.

项目摘要/摘要 Li-fraumeni综合征患者易于癌症导致癌症的癌症 抑制器，p53。 p53中突变的遗传发生在常染色体显性模式中，并导致 终生风险增加了多种恶性肿瘤，并具有很大的早期发作可能性。虽然 先前使用小鼠敲除的研究表明，p53在肾脏形成中起作用， 发育性肾脏异常与Li-Fraumeni患者中看到的p53突变有关。 初步MRI数据表明，这些患者的泌尿生殖异常发生率高于 一般人口。因此，该提案的目的是利用Xenopus胚胎评估p53的基本 在肾脏发育中的作用并产生动物模型以确定是否在li-中看到的p53突变 Fraumeni患者导致肾异常。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。该假设将进行检验 通过以下目的：目标1。评估Xenopus胚胎中p53破坏导致的肾脏缺陷。 先前的研究表明，p53-null小鼠胚胎具有发育性肾脏缺陷，包括双工 输尿管和肾发育不全。初步数据表明，类似的肾脏发育缺陷也是 当Xenopus胚胎的肾脏降低p53水平时，存在的存在，这是一种剖析的有用模型 导致发育缺陷的机制。为将来分析的基础 p53活性的分子机制，将测试p53调节肾脏分化的假设 爪蟾肾脏。这将通过针对p53的CRIS敲除p53的新颖策略来实现 爪蟾肾脏，倾斜发育特征的定量以及分析的标志物的表达 肾脏发展。 AIM 2。确定Li-Fraumeni患者中看到的p53突变是否导致肾脏 异常。初步的MRI数据表明，Li-Fraumeni患者的泌尿生殖发生率增加 异常。引起Li-Fraumeni综合征的p53突变导致的假设导致 Xenopus nephron发育将进行测试，从而产生Li-Fraumeni肾脏的动物模型 未来研究的异常。鉴于这些患者的p53突变预计会通过 功能的收益机制，这将通过针对p53变化的表达来进行 爪蟾肾脏，在其他模型中的研究将很困难且延迟。总体而言，实验 在本应用中提出的将有助于我们对p53通常影响肾单位形成的理解 以及p53中的Li-Fraumeni患者突变如何破坏此过程。

项目成果

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.

• DOI: 10.1002/dvg.23410
• 发表时间: 2021-03
• 期刊: Genesis (New York, N.Y. : 2000)
• 作者: Corkins ME;Krneta-Stankic V;Kloc M;Miller RK
• 通讯作者: Miller RK