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Modulation of cystogenesis

调节囊肿发生

基本信息

批准号：
10612962
负责人：
Jing Zhou
金额：
$ 59.71万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612962
关键词：
Actins Adult Affect Animal Disease Models Animal Model Autosomal Dominant Polycystic Kidney Biochemical Biochemistry Bioinformatics Biological Biological Models Cell model Cells Cellular biology Cilia Complement Complex Coupled Cultured Cells Cyclic AMP Cyst Cytoplasm Cytoskeletal Modeling Cytoskeleton Data Defect Development Disease Disease Progression Disease model Drug Targeting ERBB2 gene Epithelium Event Excision FRAP1 gene G-Protein-Coupled Receptors Genes Genetic Genetic Crosses Goals Growth Human Image In Vitro Individual Integrins Intercalated Cell Kidney Kidney Failure Knock-out Knockout Mice Liver Mediating Modeling Molecular Mus Mutation NF-kappa B Neonatal Neurons Pathway interactions Peptide Signal Sequences Persons Phenotype Phosphoproteins Population Control Probability Proprotein Convertase 2 Protein Deficiency Protein Kinase C Proteins Proteome Proteomics Protocols documentation Regulation Renal tubule structure Reporting Research Role STAT3 gene Signal Pathway Signal Transduction System Tamoxifen Technology Testing Therapeutic United States Vesicle Wasps bioinformatics tool casein kinase cell motility cell type clinical care comparative design directional cell experimental study gastrulation in vivo in vivo imaging innovation insight interdisciplinary approach mouse model new therapeutic target novel planar cell polarity polycystic kidney disease 1 protein postnatal protein complex protein function protein protein interaction receptor internalization receptor recycling survivin trafficking water channel

项目摘要

Mutations in PKD1 are responsible for over 85% of cases in autosomal dominant polycystic kidney disease (ADPKD). A number of studies by us and others have implicated that the ADPKD proteins polycystin-1 and -2 (PC1 and PC2) modulate a number of cellular events and signaling pathways such as Ca2+ signaling, JAK- STAT, mTOR, cyclic AMP (cAMP), and planar cell polarity (PCP). How polycystins modulate these pathways, however, remains elusive. The sequence of these signaling events is unknown. A major challenge is that many experiments have been performed using different model systems, different cell types, and under different conditions. Better understanding of the cystogenic mechanisms and disease progression of ADPKD is a high priority for clinical care. Our long-term goal of this proposal is to identify and modulate the factors controlling cyst formation and enlargement in ADPKD using multidisciplinary approaches. We previously reported a biochemical interaction between PC1 and protein kinase C and casein kinase substrate in neurons 2 (Pacsin 2), a cytoplasmic phosphoprotein that has been implicated in cytoskeletal organization and vesicle trafficking. By in vitro studies, we found that PC1, Pacsin 2 and N-Wasp are in the same protein complex and deficiency of either PC1 or Pacsin 2 leads to defects in actin cytoskeleton and cell migration in cultured cells. Here we propose to extend our study of Pacsin 2 to multiple orthologous mouse models of ADPKD that we have developed to understand mechanisms suppressing cystogenesis. We aim to develop an in vivo imaging protocol of cell migration and to elucidate the role of Pascin 2 in cystogenesis using multidisciplinary approaches including the analysis the cystogenic proteome and phosphoproteome in human and mouse ADPKD models using the latest quantitative proteomics technology, coupled with innovative bioinformatics tools. The proposed studies will likely discover novel therapeutic targets central to the early event(s) in cystogenesis.

超过85%的常染色体显性遗传性多囊肾病患者与PKD1基因突变有关 (ADPKD)。我们和其他人的一些研究表明，ADPKD蛋白多囊蛋白-1和-2 (PC1和PC2)调节一系列细胞事件和信号通路，如钙信号、JAK- STAT、mTOR、环磷酸腺苷(CAMP)和平面细胞极性(PCP)。多囊蛋白是如何调节这些通路的，然而，这一点仍然难以捉摸。这些信号事件的顺序是未知的。一个主要的挑战是许多使用不同的模型系统、不同的细胞类型和不同的条件下进行了实验条件。对ADPKD的囊变机制和疾病进展有更好的了解是非常重要的优先考虑临床护理。我们这项提议的长期目标是识别和调节控制因素多学科方法在ADPKD中的囊性形成和扩大。我们之前曾报道过 PC1与蛋白激酶C和酪蛋白激酶底物的生化相互作用 2)，一种与细胞骨架组织和囊泡运输有关的细胞质磷酸蛋白。通过体外研究，我们发现PC1、Pacsin 2和N-Wasp处于相同的蛋白质复合体中，但缺乏 PC1或Pacsin 2的缺失会导致培养细胞中肌动蛋白细胞骨架的缺陷和细胞迁移。在这里我们建议将我们对Pacsin 2的研究扩展到我们已有的多种ADPKD直系小鼠模型为了了解抑制囊变的机制而发展起来的。我们的目标是开发一种活体成像细胞迁移协议及多学科研究Pascin 2在囊变发生中的作用分析人和小鼠的成囊蛋白质组和磷酸蛋白质组的方法 ADPKD模型使用最新的定量蛋白质组学技术，结合创新的生物信息学工具。拟议的研究可能会发现囊变早期事件(S)的核心新的治疗靶点。