Role of LRP1 in Podocyte Biology

LRP1 在足细胞生物学中的作用

• 批准号: 10734512
• 负责人: Shuta Ishibe
• 金额: $ 43.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734512
• 关键词: Address; Affect; Agonist; Applications Grants; Area; Biological; Biology; Cell Count; Cell Culture Techniques; Cell Cycle; Cell Differentiation process; Cell Size; Chronic Kidney Failure; Clathrin; Clathrin-Coated Vesicles; DNA Repair; DNA Sequence Alteration; Data; Databases; Deterioration; Development; Dialysis procedure; Disease model; Doxycycline; Effectiveness; End stage renal failure; Endosomes; Endothelial Cells; Evaluation; Excretory function; FDA approved; Failure; Filtration; Functional disorder; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Grant; Guanosine; Human; Human Genetics; Impairment; In Vitro; Information Systems; Injury; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knock-out; Knockout Mice; Ligands; Lipoprotein Receptor; Maintenance; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Modality; Modeling; Molecular; Mus; Nephrotic Syndrome; Nonhomologous DNA End Joining; Pathogenesis; Pathologic; Pathway interactions; Patients; Play; Population; Positioning Attribute; Proteins; Proteinuria; Proteomics; Public Health; Regulation; Renal function; Renal glomerular disease; Residual state; Role; Secondary to; Shotguns; Signal Pathway; Signal Transduction; Small Interfering RNA; Steroid-resistant idiopathic nephrotic syndrome; Testing; Therapeutic; United States; Urine; Water; ds-DNA; experimental study; gene repair; genetic approach; glomerular basement membrane; glomerular filtration; glomerular function; in vivo; knock-down; lipoprotein receptor related protein 5; mouse model; new therapeutic target; novel; pharmacologic; podocyte; precision medicine; prevent; repaired; solute; tandem mass spectrometry; trafficking; transcriptome sequencing; urinary; wasting

Project Summary Chronic kidney disease (CKD) often leads to irreversible deterioration of kidney function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that 20 million patients in the United States suffer from CKD. As glomerular diseases secondary to podocyte dysfunction account for greater than 80% of all CKD, an intensive molecular and genetic approach to identify mechanisms for podocyte development, maintenance and repair may provide new therapeutic targets Previous evidence has suggested the importance of endocytic trafficking in podocytes, Using a unbiased screen, we have unearthed Lrp1 within clathrin coated vesicles, and as a potentially important gene to maintain the integrity of the glomerular filtration barrier. Loss of Lrp1 specifically in mice podocytes resulted in proteinuria and progression of CKD. Therefore, In Aim 1, we will define the fundamental mechanisms on how loss of Lrp1 contributes to podocyte dysfunction through characterizing the newly generated knockout mice. In Aim 2, we will determine how Lrp1 signaling plays a potential role in dsDNA repair by examining genes critical for nonhomologous end joining Setd1a and Lig4, and test SP16, a FDA approved Lrp1 agonist in the treatment of mouse models of glomerular injury.

项目概要 慢性肾病（CKD）通常会导致肾功能不可逆转的恶化 通常会进展为终末期肾病 (ESKD)。 CKD 已成为 严重的公共卫生问题和从 USRDS 获得的数据显示，2000 万人 美国的患者患有 CKD。由于继发于肾小球疾病 足细胞功能障碍占所有 CKD 的 80% 以上，这是一种密集的分子机制 和遗传方法来确定足细胞发育、维持的机制 和修复可能提供新的治疗靶点 先前的证据表明 足细胞内吞运输的重要性，使用无偏见的筛选，我们有 在网格蛋白包被的囊泡中发现了Lrp1，并且作为一个潜在的重要基因 维持肾小球滤过屏障的完整性。 Lrp1 在小鼠中的缺失 足细胞导致蛋白尿和 CKD 进展。因此，在目标 1 中，我们将 定义 Lrp1 缺失如何影响足细胞的基本机制 通过表征新产生的基因敲除小鼠的功能障碍。在目标 2 中，我们将 通过检查基因确定 Lrp1 信号传导如何在 dsDNA 修复中发挥潜在作用 对于非同源末端连接 Setd1a 和 Lig4 至关重要，并测试 SP16（FDA 批准的） Lrp1 激动剂治疗小鼠肾小球损伤模型。

项目成果

Podocyte endocytosis in the regulation of the glomerular filtration barrier.

足细胞内吞作用调节肾小球滤过屏障。

• DOI: 10.1152/ajprenal.00136.2015
• 发表时间: 2015-09-01
• 期刊: American journal of physiology. Renal physiology
• 作者: Kazunori Inoue;S. Ishibe
• 通讯作者: S. Ishibe

Cell Cycle and Senescence Regulation by Podocyte Histone Deacetylase 1 and 2.

足细胞组蛋白脱乙酰酶 1 和 2 的细胞周期和衰老调节。

• 发表时间: 2023-03-01
• 作者: Medina Rangel, Paulina X;Cross, Elizabeth;Liu, Chang;Pedigo, Christopher E;Tian, Xuefei;Gutiérrez;Nagata, Soichiro;Priyadarshini, Anupama;Lerner, Gabriel;Bunda, Patricia;Perincheri, Sudhir;Gu, Jianlei;Zhao, Hongyu;Wang, Ying
• 通讯作者: Wang, Ying

Identification of Podocyte Cargo Proteins by Proteomic Analysis of Clathrin-Coated Vesicles.

通过网格蛋白包被的囊泡的蛋白质组学分析鉴定足细胞货物蛋白。

• DOI: 10.34067/kid.0000212020
• 发表时间: 2020-04-16
• 期刊: Kidney360
• 作者: Marwin Groener;Ying Wang;Elizabeth Cross;Xuefei Tian;Karen Ebenezer;E. Baik;C. Pedigo;M. Schiffer;Kazunori Inoue;S. Ishibe
• 通讯作者: S. Ishibe

Inhibition of podocyte FAK protects against proteinuria and foot process effacement.

足细胞 FAK 的抑制可防止蛋白尿和足突消失。

• DOI: 10.1681/asn.2009090991
• 发表时间: 2010-07-01
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Hong Ma;A. Togawa;K. Soda;Junhui Zhang;Sik Lee;Ming Ma;Zhiheng Yu;T. Ardito;J. Czyzyk;Lonnette Diggs;D. Joly;S. Hatakeyama;E. Kawahara;L. Holzman;J. Guan;S. Ishibe
• 通讯作者: S. Ishibe

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.

Profilin1 对于预防小鼠和人类肾小球疾病的有丝分裂灾难是必需的。

• 发表时间: 2023-12-15
• 作者: Tian, Xuefei;Pedigo, Christopher E;Li, Ke;Ma, Xiaotao;Bunda, Patricia;Pell, John;Lek, Angela;Gu, Jianlei;Zhang, Yan;Medina Rangel, Paulina X;Li, Wei;Schwartze, Eike;Nagata, Soichiro;Lerner, Gabriel;Perincheri, Sudhir;Priyadarshini, Anupama
• 通讯作者: Priyadarshini, Anupama