Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease.
Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease.
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DOI：
10.1093/hmg/ddt103
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发表时间：
2013-07-01
影响因子：
3.5
通讯作者：
Brown SD
中科院分区：
文献类型：
--
作者：
Tateossian H;Morse S;Parker A;Mburu P;Warr N;Acevedo-Arozena A;Cheeseman M;Wells S;Brown SD
渗出性中耳炎(OME)是儿童听力损失的最常见原因，在发达国家，鼓膜切开术仍然是儿童最常见的手术治疗。众所周知，慢性和复发性OM具有非常重要的遗传成分，然而，直到最近，人们对涉及的潜在基因知之甚少。对慢性OM小鼠模型的鉴定表明，转化生长因子β(转化生长因子β)信号的作用及其对炎症中耳对低氧反应的影响。因此，我们研究了转化生长因子β信号的作用，并鉴定和鉴定了一种新的慢性OM模型，该模型携带转化生长相互作用因子1(TGF1)基因的突变。Tgif1纯合子突变小鼠显著提高了听力阈值，这是由于大约3周大的慢性渗出性耳聋引起的传导性耳聋。OM伴有中耳黏膜衬里明显增厚，分泌粘蛋白的杯状细胞增多，耳液中血管内皮生长因子、肿瘤坏死因子-α和白介素1-β水平升高。我们还确定了慢性OM发生时，转化生长因子β信号在中耳上皮细胞中的下游作用。在纯合子突变体中，磷酸化的Smad2和p21的水平都降低了，表明转化生长因子β途径受到抑制。TGIF突变体的鉴定和鉴定支持转化生长因子β信号在慢性OM发生发展中的作用，并为人类群体遗传学研究提供了一个重要的候选基因。
Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFβ) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFβ signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-α and IL-1β in ear fluids. We also identified downstream effects on TGFβ signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFβ pathway. The identification and characterization of the Tgif mutant supports the role of TGFβ signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population.
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影响因子：
3.7
作者：
Mburu P;Romero MR;Hilton H;Parker A;Townsend S;Kikkawa Y;Brown SD
通讯作者：
Brown SD
影响因子：
19.6
作者：
Levy, AP;Levy, NS;Goldberg, MA
通讯作者：
Goldberg, MA
影响因子：
2.7
作者：
Bartholin, Laurent;Melhuish, Tiffany A.;Wotton, David
通讯作者：
Wotton, David
影响因子：
11.4
作者：
Faresse, Nourdine;Colland, Frederic;Atfi, Azeddine
通讯作者：
Atfi, Azeddine
影响因子：
5.4
作者：
Holland PW;Booth HA;Bruford EA
通讯作者：
Bruford EA