Mining a microRNA Regulated Gene Network to Rescue CFTR-DeltaF508 Function

描述（由申请人提供）：在发现囊性纤维化（CF）的遗传基础20年后，我们没有新的疗法可以恢复与最常见疾病形式相关的突变蛋白的功能。大部分CF相关的发病率和死亡率由进行性肺部感染和炎症引起。最常见的CFTR突变，即F508，存在于约70%的突变等位基因上，并导致蛋白质错误折叠，导致蛋白质体降解。我们发现了一种新的microRNA（miRNA）调控的基因网络，它影响CFTR的转录和加工，并恢复CFTR-β F508在气道上皮细胞中的功能。MiR-138通过与转录调节蛋白SIN 3A相互作用来调节CFTR表达。SIN 3A抑制改变 编码与CFTR相关并可能影响其生物合成的蛋白质的基因的表达。操纵这一调控网络可以改善CFTR-β F508的生物合成，并恢复CF气道上皮细胞的Cl-转运.该提案利用我们对SIN 3A调控基因网络的了解来设计CF的新疗法。我们将：1）鉴定负责CFTR-β F508拯救的关键SIN 3A调节基因产物; 2）使用SIN 3A介导的CFTR-β F508拯救的基因组特征来鉴定治疗剂; 3）使用先导化合物来拯救具有β F508突变的新生猪的CFTR功能。这些互补的策略应该为CFTR生物合成所涉及的细胞途径提供新的见解，并为鉴定CFTR-β F508校正剂提供新的方法。

DESCRIPTION (provided by applicant): Twenty years after the discovery of the genetic basis of cystic fibrosis (CF) was identified, we have no new therapies that can restore function to the mutant protein associated with the most common form of the disease. The majority of CF-associated morbidity and mortality arises from progressive pulmonary infection and inflammation. The most common CFTR mutation, �F508, is present on ~70% of mutant alleles and causes protein misfolding, leading to proteosomal degradation. We discovered a novel microRNA (miRNA)-regulated gene network that influences CFTR transcription and processing, and restores CFTR-�F508 function in airway epithelia. MiR-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. SIN3A inhibition alters the expression of genes encoding proteins that associate with CFTR and may influence its biosynthesis. Manipulating this regulatory network improves CFTR-�F508 biosynthesis and restores Cl- transport to CF airway epithelia. This proposal leverages our knowledge of the SIN3A-regulated gene network to design new therapies for CF. We will: 1) Identify the key SIN3A-regulated gene products responsible for CFTR-�F508 rescue; 2) Use the genomic signatures of SIN3A-mediated CFTR-�F508 rescue to identify therapeutic agents; and 3) Use lead compounds to rescue CFTR function in newborn pigs with the �F508 mutation. These complementary strategies should provide new insights into the cellular pathways involved in CFTR biosynthesis and offer new approaches for identifying CFTR-�F508 correctors.