Ciliary Disassembly, a modifier of Autosomal Dominant Polycystic Kidney Disease

常染色体显性遗传性多囊肾病(ADPKD)是最常见的遗传性疾病之一 全世界有1250万人，到目前为止，肾脏是最常见的遗传病。是由以下原因引起的 PKD1或PKD2基因的失活突变，编码受体-通道复合体(多囊蛋白或 PK1/PKD2)。ADPKD的一个特点是细胞增殖增加。然而，多囊蛋白中的突变是如何 基因导致细胞增殖增加的原因还不完全清楚。疾病发展中的一个关键细胞器 而PROCESS是初级纤毛，一个类似天线的细胞器，包含几个有丝分裂信号通路。 遗传学和药理学研究表明，初级纤毛消融或加速纤毛分解会减少 细胞增殖，抑制囊性生长，改善肾功能，而纤毛减速 在ADPKD小鼠模型中，拆卸具有相反的效果。虽然这些观察是最重要的 了解ADPKD的病理生理学和开发慢性病的治疗方法的重要性 在ADPKD中，缺乏将纤毛和细胞增殖联系起来的统一理论。纤毛 组装和分解或脱落是活跃增殖细胞的正常过程。纤毛聚集在一起 静止的细胞，当细胞重新进入细胞周期时解体或脱落(G1/S)。我们的初步数据显示 PKD1的缺失增加了P53的活性/水平，进而诱导底物的表达 SCFFBW7泛素E3连接酶识别受体FBW7。Fbw7蛋白酶体降解靶标a 分解因子的子集，延缓腐烂和稳定初生纤毛。纤毛持续存在 在G1/S转换过程中，稳定的纤毛/剩余纤毛介导持续的有丝分裂信号 更多的细胞最终进入细胞周期。最后，对这一途径进行基因改造，改善肾脏 蛋白激酶1基因缺失小鼠的功能。这些结果有助于解释ADPKD肾脏细胞增殖增加的原因。 纤毛对疾病进展的积极作用。使用垂直方法结合生化、细胞 生物学和遗传学方法，我们将确定纤毛分解和脱落在囊性肾中的作用 疾病的发展。成功完成拟议的工作将对我们的理解产生重大影响 纤毛分解/脱落在疾病进展中的生物学作用和帮助发展新的 ADPKD的治疗方法。

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.