Ciliary Disassembly, a modifier of Autosomal Dominant Polycystic Kidney Disease

纤毛分解，常染色体显性多囊肾病的修饰因子

基本信息

批准号：
10094363
负责人：
Leonidas Tsiokas
金额：
$ 35.63万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094363
关键词：
Ablation Acceleration Affect Autosomal Dominant Polycystic Kidney Biochemical Biological CRISPR screen Cell Cycle Cell Cycle Progression Cell Proliferation Cells Cilia Complex Cyst Cystic Kidney Diseases Cystic kidney Data Deceleration Development Disease Disease Progression Epithelial Exposure to FBXW7 gene Functional disorder G1/S Transition Genes Genetic Genetic Diseases Genetic study Growth HDAC6 gene Housing Kidney Diseases Knockout Mice Mediating Methods Mitosis Mitotic Modeling Modification Mus Mutation Names Null Lymphocytes Organelles PKD1 gene PKD2 gene Pathway interactions Pharmacology Pharmacology Study Process Proliferating Renal function Role Serum Signal Pathway Signal Transduction Stimulus TP53 gene Therapeutic Time Work cell type design genome-wide improved mouse model mutant novel therapeutic intervention p53-binding protein 1 receptor theories ubiquitin-protein ligase

项目摘要

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common genetic diseases affecting 12.5 million people worldwide and by far, the most common genetic disease of the kidney. It is caused by inactivating mutations in the PKD1 or PKD2 genes, encoding a receptor-channel complex (Polycystins or PKD1/PKD2). A hallmark of ADPKD is increased cell proliferation. However, how mutations in the Polycystin genes cause increased cell proliferation is not completely understood. A key organelle in disease development and progression is the primary cilium, an antenna-like organelle housing several mitogenic signaling pathways. Genetic and pharmacologic studies show that primary cilia ablation or acceleration of cilia disassembly reduces cell proliferation, suppresses cystic growth and improves kidney function, whereas deceleration of ciliary disassembly has the opposite effects in mouse models of ADPKD. While these observations are of paramount importance in understanding the pathophysiology of ADPKD and in developing therapeutic approaches to slow down disease progression, a unifying theory connecting cilia and cell proliferation in ADPKD is lacking. Ciliary assembly and disassembly or shedding are normal processes of actively proliferating cells. Cilia assemble in quiescent cells, while disassemble or shed when cells re-enter the cell cycle (G1/S). Our preliminary data show that deletion of Pkd1 increases the activity/levels of p53, which in turn, induces the expression of the substrate recognition receptor FBW7 of the SCFFBW7 Ubiquitin E3 ligase. FBW7 targets for proteasomal degradation a subset of disassembly factors delaying deciliation and stabilizing primary cilia. Continuous presence of cilia during the G1/S transition leads to sustained mitogenic signaling mediated by stabilized/remaining cilia resulting in more cells eventually entering the cell cycle. Finally, genetic modifications of this pathway, improve renal function of Pkd1-null mice. These results help explain the increased cell proliferation seen in ADPKD kidneys and the positive effect of cilia on disease progression. Using a vertical approach combining biochemical, cell biological, and genetic methods, we will determine the role of ciliary disassembly and shedding in cystic kidney disease progression. Successful completion of the proposed will have a significant impact on our understanding the biological role of ciliary disassembly/shedding in disease progression and on helping develop new therapeutic approaches for ADPKD.

常染色体显性多囊性肾脏疾病（ADPKD）是影响的最常见遗传疾病之一全世界有1,250万人，到目前为止，是肾脏最常见的遗传疾病。它是由 PKD1或PKD2基因中的灭活突变，编码受体通道复合物（Polycystins或 PKD1/PKD2）。 ADPKD的标志是细胞增殖增加。但是，多囊突变如何基因导致细胞增殖的增加尚不完全了解。疾病发育中的关键细胞器进展是原发性纤毛，是一种天线样细胞器，具有几种有丝分裂信号通路。遗传学和药理学研究表明，纤毛的原发性纤毛消融或加速纤毛拆卸会减少细胞增殖，抑制囊性生长并改善肾功能，而纤毛减速拆卸在ADPKD的小鼠模型中具有相反的影响。这些观察是最重要的在理解ADPKD的病理生理和开发治疗方法以减慢的方法方面的重要性疾病进展，缺乏连接纤毛的统一理论和ADPKD中的细胞增殖。纤毛组装和拆卸或脱落是主动增殖细胞的正常过程。纤毛组合静止的细胞，而当细胞重新输入细胞周期（G1/s）时，静止或脱落。我们的初步数据显示 PKD1的删除增加了p53的活性/水平，从而诱导底物的表达 SCFFBW7泛素E3连接酶的识别受体FBW7。 FBW7蛋白酶体降解的靶标拆卸因素的子集延迟了衰减和稳定原发性纤毛。连续存在纤毛在G1/s转变期间，导致稳定/剩余的纤毛介导的持续有丝分裂信号传导，导致在更多的细胞中，最终进入细胞周期。最后，该途径的遗传修饰，改善肾脏 PKD1-NULL小鼠的功能。这些结果有助于解释ADPKD肾脏中发现的细胞增殖增加以及纤毛对疾病进展的积极作用。使用结合生化细胞的垂直方法生物学和遗传方法，我们将确定纤毛拆卸和脱落在囊性肾脏中的作用疾病进展。成功完成拟议的完成将对我们的理解产生重大影响睫状分解/脱落在疾病进展中的生物学作用以及帮助发展新的 ADPKD的治疗方法。