Control of airway inflammation and Th2 differentiation by microRNA 21

描述（由申请人提供）：Th2细胞介导的特应性和过敏性疾病的发病率在世界范围内急剧增加，几乎50%的城市人口患有特应性疾病，包括哮喘、鼻结膜炎、鼻窦炎、食物过敏和特应性皮炎。因此，过敏性疾病的新诊断标志物和治疗仍然是高度优先事项。微小RNA（miRs）是基因表达的重要调节因子，并且特别地，miRs关键地控制免疫系统功能。miR在许多病理条件下是失调的，并且miR已经在癌症和与癌症相关的炎症中被广泛研究。miR在其他类型炎症中的作用是一个相对较新的研究领域，关于miR在过敏性疾病和过敏性炎症中的作用知之甚少。发现MiR21在Th2型过敏性炎症的肺中高度上调，我们最近发现肺中更严重的过敏性炎症与miR21表达的强烈增加相关。我们已经进一步确定T细胞中增加的miR21表达可以促进Th2分化。因此，我们假设在炎症条件下，高miR21表达促进进一步炎症和扩增的Th2分化。这一假设预测阻断miR21可以减轻Th2型炎症，在本提案中，我们将测试miR21抑制作为过敏性疾病的潜在疗法。我们将通过阐明miR21促进Th2分化的机制，进一步确定miR21在Th2分化和炎症中的作用。我们还将分析哪些特定的细胞类型在炎症过程中上调miR21。miR 21的转录由活化的STAT 3诱导，我们已经确定miR 21的转录被BCL 6抑制。我们将探讨BCL 6对miR 21的抑制与STAT 3激活的关系，以及是否存在STAT 3和BCL 6对miR 21的拮抗调节，从而控制Th2分化。这些研究有可能导致过敏性疾病的新治疗方法，并为过敏和特应性的致病机制提供新的见解。

DESCRIPTION (provided by applicant): The incidence of Th2 cell-mediated atopic and allergic diseases are increasing dramatically worldwide, with almost 50% of the urban population presenting with atopic diseases including asthma, rhino- conjunctivitis, sinusitis, food allergy, and atopic dermatitis. Thus, new diagnostic markers and treatments for allergic diseases remain a high priority. Micro-RNAs (miRs) are important regulators of gene expression, and in particular, miRs critically control immune system function. MiRs are deregulated in many pathologic conditions, and miRs have been studied extensively in cancer and the inflammation associated with cancer. The role of miRs in other types of inflammation is a relatively new area of investigation, and little is known about miRs in allergic disease and allergic inflammation. MiR21 was found to be highly up-regulated in lungs with Th2-type allergic inflammation, and we recently have found that more severe allergic inflammation in the lung correlates with strongly increased miR21 expression. We have further established that increased miR21 expression in T cells can promote Th2 differentiation. Thus, we hypothesize that during inflammatory conditions, high miR21 expression promotes further inflammation and amplified Th2 differentiation. This hypothesis predicts that blocking miR21 can alleviate Th2-type inflammation, and in this proposal we will test miR21 inhibition as a potential therapy for allergic disease. We will further define the role of miR21 in Th2 differentiation and inflammation, by elucidating the mechanism by which miR21 promotes Th2 differentiation. We will also analyze what specific cell types up-regulate miR21 during inflammation. MiR21 transcription is induced by activated STAT3, and we have determined that miR21 transcription is repressed by BCL6. We will explore the relationship of BCL6 repression of miR21 to activation by STAT3, and if there is an antagonistic regulation of miR21 by STAT3 and BCL6 that controls Th2 differentiation. These studies have the potential to lead to new treatments for allergic disease, as well as provide novel insights into the pathogenic mechanisms of allergy and atopy.