Department of Surgery/Otolaryngology, UC San Diego, San Diego, CA, United States of America.
School of Medicine, UC San Diego, San Diego, CA, United States of America.
PLoS One. 2020 Aug 6;15(8):e0235634. doi: 10.1371/journal.pone.0235634. eCollection 2020.
Otitis media, the most common disease of childhood, is characterized by extensive changes in the morphology of the middle ear cavity. This includes hyperplasia of the mucosa that lines the tympanic cavity, from a simple monolayer of squamous epithelium into a greatly thickened, respiratory-type mucosa. The processes that control this response, which is critical to otitis media pathogenesis and recovery, are incompletely understood. Given the central role of protein phosphorylation in most intracellular processes, including cell proliferation and differentiation, we screened a library of kinase inhibitors targeting members of all the major families in the kinome for their ability to influence the growth of middle ear mucosal explants in vitro. Of the 160 inhibitors, 30 were found to inhibit mucosal growth, while two inhibitors enhanced tissue proliferation. The results suggest that the regulation of infection-mediated tissue growth in the ME mucosa involves multiple cellular processes that span the kinome. While some of the pathways and processes identified have been previously implicated in mucosa hyperplasia others are novel. The results were used to generate a global model of growth regulation by kinase pathways. The potential for therapeutic applications of the results are discussed.
中耳炎是儿童最常见的疾病，其特征是中耳腔形态发生广泛变化。这包括鼓膜腔衬里的黏膜增生，由单层扁平上皮变为明显增厚的呼吸型黏膜。控制这种反应的过程对于中耳炎的发病机制和恢复至关重要，但目前还不完全了解。鉴于蛋白质磷酸化在大多数细胞内过程（包括细胞增殖和分化）中的核心作用，我们筛选了一个针对激酶组中所有主要家族成员的激酶抑制剂文库，以研究它们抑制中耳黏膜外植体体外生长的能力。在 160 种抑制剂中，有 30 种被发现可以抑制黏膜生长，而有两种抑制剂可以增强组织增殖。结果表明，感染介导的 ME 黏膜组织生长的调节涉及多个细胞过程，涵盖了整个激酶组。虽然已经确定了一些通路和过程与黏膜增生有关，但其他过程是新的。结果被用来生成一个由激酶通路调节生长的全局模型。讨论了结果的潜在治疗应用。
