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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：
10549844
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/10549844
关键词：
Ablation Acceleration Affect Autosomal Dominant Polycystic Kidney Biochemical Biological CRISPR screen Cell Cycle Cell Cycle Progression Cell Proliferation Cells Centrosome Cilia Complex Cyst Cystic Kidney Diseases Cystic kidney Data Deceleration Development Disease Disease Progression Epithelium 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 Persons 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 pharmacologic 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.

常染色体显性遗传性多囊肾病（ADPKD）是影响人类健康的最常见的遗传性疾病之一。 12.5这是迄今为止最常见的肾脏遗传疾病。由它造成 PKD 1或PKD 2基因中的失活突变，编码受体通道复合物（多囊蛋白或 PKD 1/PKD 2）。ADPKD的标志是细胞增殖增加。然而，多囊蛋白的突变导致细胞增殖增加的基因尚未完全了解。疾病发展中的关键细胞器和进展是初级纤毛，一个触角样的细胞器住房几个促有丝分裂的信号通路。遗传学和药理学研究表明，初级纤毛消融或加速纤毛解体会减少细胞增殖，抑制囊性生长，改善肾功能，而纤毛减速拆卸在ADPKD小鼠模型中具有相反的效果。虽然这些意见至关重要，重要的是了解ADPKD的病理生理学和开发治疗方法，随着疾病进展，缺乏一个将ADPKD中纤毛和细胞增殖联系起来的统一理论。睫状组装和分解或脱落是活跃增殖细胞的正常过程。纤毛聚集在静止细胞，而当细胞重新进入细胞周期（G1/S）时分解或脱落。我们的初步数据显示 Pkd 1的缺失增加了p53的活性/水平，这反过来又诱导了底物的表达， SCFFBW 7泛素E3连接酶的识别受体FBW 7。蛋白酶体降解的FBW 7靶标a 延迟脱附和稳定初级纤毛的分解因子的子集。纤毛持续存在在G1/S转换期间，导致由稳定/剩余纤毛介导的持续促有丝分裂信号传导，更多的细胞最终进入细胞周期。最后，对这一途径进行遗传修饰， Pkd 1-null小鼠的功能。这些结果有助于解释ADPKD肾脏中细胞增殖增加以及纤毛对疾病进展的积极作用。使用垂直方法结合生物化学，细胞生物学和遗传学方法，我们将确定睫状体解体和脱落在囊性肾中的作用疾病进展。成功完成拟议将对我们的理解产生重大影响睫状体分解/脱落在疾病进展中的生物学作用以及帮助开发新的 ADPKD的治疗方法