MicroRNAs: New Regulators of Disease Progression in Polycystic Kidney Disease

 描述（由申请人提供）：ADPKD的特征是存在大量充满液体的囊肿，随着时间的推移，囊肿的大小会增加，并导致肾衰竭。尽管最近取得了进展，但ADPKD的发病机制尚未完全了解，并且没有FDA批准的药物可用。大多数ADPKD患者由于PKD 1或2的功能完全丧失而形成囊肿。然而，新的证据表明，一些ADPKD患者具有亚型突变，并且由于PKD 1或2基因剂量减少而形成囊肿。另一个新的主题是，减少剂量的几个基因产物内的“囊性途径”的adPKD表型。这些观察结果表明，提高PKD 1，PKD 2和其他“囊性途径基因”的表达代表了一个令人兴奋的新的治疗机会，以抑制囊肿生长。在这方面，miRNA是独特的药物靶标，因为它们可以被抑制以同时增加多囊性途径基因的表达。原理：miRNAs在ADPKD中的作用在很大程度上尚未探索。我们最近表明：（i）miR-17~92在PKD模型中上调;（ii）正常小鼠中miR-17~92的肾脏特异性过表达产生囊肿;以及（iii）重要的是，在PKD小鼠模型中抑制miR-17~92抑制囊肿生长。有趣的是，许多囊性肾病基因被预测为miR-17~92靶点。因此，抑制miR-17~92可能成为PKD治疗的新策略。然而，验证miR-17~92作为治疗靶点需要在类似于成人发病、缓慢生长囊肿的人类ADPKD表型的正常小鼠模型中研究其作用。假设：miR-17~92水平的增加通过减少囊性途径中多个基因产物的剂量来促进ADPKD中的囊肿生长。目标：我们将使用互补的遗传学和药物学方法来确定抑制miR-17~92是否会延缓囊肿生长并增加ADPKD的原位模型中靶向囊性肾病基因的表达。为了提供与人类疾病的相关性，我们将确定在人类ADPKD样本中miR- 17~92是否上调以及囊性肾病靶基因是否下调。最后，我们将确定miR-17介导的Pkd 1和Pkd 2抑制是否足以促进体内囊肿生长。

 DESCRIPTION (provided by applicant): ADPKD is characterized by the presence of numerous fluid-filled cysts, which grow in size over time and produce kidney failure. Despite recent progress, pathogenesis of ADPKD is not fully understood, and no FDA-approved drugs are available. Majority of ADPKD patients develop cysts due to complete loss-of- function of PKD1 or 2. However, new evidence indicates that some ADPKD patients harbor hypomorphic mutations, and they develop cysts due to reduced PKD1 or 2 gene dosage. Another new theme is that reduced dosage of several gene products within the `cystic pathway' aggravates the ADPKD phenotype. These observations suggest that improving the expression of PKD1, PKD2 and other `cystic pathway genes' represents an exciting new therapeutic opportunity to suppress cyst growth. miRNAs are unique drug targets in this regard as they can be inhibited to simultaneously increase the expression of multiple cystic pathway genes. RATIONALE: The role of miRNAs in ADPKD largely remains unexplored. We have recently showed that: (i) miR-17~92 is up-regulated in models of PKD; (ii) kidney-specific overexpression of miR-17~92 in normal mice produces cysts; and (iii) importantly, inhibition of miR-17~92 in a mouse model of PKD suppresses cyst growth. Interestingly, many cystic kidney disease genes are predicted to be miR-17~92 targets. Thus, inhibition of the miR-17~92 may be a potential new therapeutic strategy for PKD. However, validating miR-17~92 as a therapeutic target requires that its role is studied in orthologous mouse models that resemble the human ADPKD phenotype of adult-onset, slowly-growing cysts. HYPOTHESIS: Increased levels of miR-17~92 promote cyst growth in ADPKD by reducing the dosage of multiple gene products in the cystic pathway. AIMS: We will use complementary genetic and pharmaceutical approaches to determine whether inhibition of miR-17~92 retards cyst growth and increases the expression of target cystic kidney disease genes in orthologous models of ADPKD. To provide relevance to human disease, we will determine whether miR- 17~92 is up-regulated and the target cystic kidney disease genes are downregulated in human ADPKD samples. Finally, we will determine whether miR-17-mediated inhibition of Pkd1 and Pkd2 is sufficient and necessary to promote cyst growth in vivo.