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Modulation of cystogenesis

囊肿发生的调节

基本信息

批准号：
10446085
负责人：
Jing Zhou
金额：
$ 61.69万
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/10446085
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 Cytoskeletal Modeling Cytoskeleton Data Defect Development Disease Disease Progression Disease model Drug Targeting ERBB2 gene Epithelial Event Excision FRAP1 gene G-Protein-Coupled Receptors Genes Genetic Genetic Crosses Goals Growth Human Image In Vitro Individual Integrins Kidney Kidney Failure Knock-out Knockout Mice Liver Mediating Modeling Molecular Mus Mutation Neonatal Neurons Pathway interactions Peptide Signal Sequences Persons Phenotype Phosphoproteins Population 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 intercalation interdisciplinary approach mouse model new therapeutic target novel planar cell polarity polycystic kidney disease 1 protein postnatal protein complex 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% 的常染色体显性多囊肾病病例是由 PKD1 突变引起的（ADPKD）。我们和其他人的大量研究表明 ADPKD 蛋白多囊蛋白-1 和 -2 （PC1 和 PC2）调节许多细胞事件和信号传导途径，例如 Ca2+ 信号传导、JAK- STAT、mTOR、环磷酸腺苷 (cAMP) 和平面细胞极性 (PCP)。多囊蛋白如何调节这些途径，然而，仍然难以捉摸。这些信号事件的顺序未知。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、在不同的条件下进行了实验状况。更好地了解 ADPKD 的囊肿机制和疾病进展具有重要意义优先考虑临床护理。我们该提案的长期目标是识别和调节控制因素使用多学科方法治疗 ADPKD 囊肿形成和扩大。我们之前报道过一个 PC1 与神经元 2 中蛋白激酶 C 和酪蛋白激酶底物之间的生化相互作用（Pacsin 2)，一种细胞质磷蛋白，与细胞骨架组织和囊泡运输有关。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物和缺陷中 PC1 或 Pacsin 2 的缺失会导致培养细胞中肌动蛋白细胞骨架和细胞迁移的缺陷。在这里我们提议将我们对 Pacsin 2 的研究扩展到我们拥有的多个 ADPKD 直系同源小鼠模型旨在了解抑制囊肿发生的机制。我们的目标是开发一种体内成像细胞迁移方案并利用多学科阐明 Pascin 2 在囊肿发生中的作用方法包括分析人和小鼠的囊原性蛋白质组和磷酸化蛋白质组 ADPKD 模型采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对膀胱发生早期事件至关重要的新治疗靶点。