MicroRNAs, inflammation, and acute lung injury.

描述（由申请人提供）：MicroRNAs是一类21-22核苷酸的非编码小rna，是基因表达的重要调节因子，已被证明可以调节广泛的细胞和发育事件。我们发现，在LPS刺激的细胞中，miR147的表达上调，并且miR147具有抗炎特性，从而减少巨噬细胞的活化。因此，我们的数据表明，特定的microrna参与调节急性TLR4诱导的炎症事件，并且microrna的调节可能对危及生命的炎症状况（如ALI）具有潜在的治疗益处。我们的假设是，miR147参与了急性炎症反应的调节，并在决定ALI的发展、持续和严重程度方面发挥了重要作用。我们的具体目标是：1)通过描绘LPS诱导miR147表达上调的机制，阐明miR147在LPS诱导的细胞活化中的作用，描绘miR147影响LPS诱导的细胞活化的机制，表征miR147在TLR4诱导的炎症反应中的作用。2)通过测定LPS处理小鼠肺中miR147的表达，探讨调节miR147的表达是否能减轻LPS诱导的ALI。拟议的研究不仅应该提高对导致ALI的细胞机制的理解，而且还可能提出旨在降低ALI发病率和/或严重程度的新型治疗干预措施。

DESCRIPTION (provided by applicant): MicroRNAs, a class of 21-22 nucleotide non-coding small RNAs, are important regulators of gene expression and have been shown to modulate a broad range of cellular and developmental events. We have found that the expression of miR147 is upregulated in LPS stimulated cells and miR147 has anti-inflammatory properties which diminish activation in macrophages. Our data therefore suggest that specific microRNAs participate in regulating acute TLR4 induced inflammatory events and that modulation of microRNAs may have potential therapeutic benefit in life-threatening inflammatory conditions, such as ALI. Our hypothesis is that miR147 participates in the regulation of acute inflammatory responses and play a major role in determining the development, perpetuation, and severity of ALI. Our specific aims are: 1) To characterize the role of miR147 in regulating TLR4 induced inflammatory responses by delineating the mechanisms leading to LPS induced upregulation in the expression of miR147, elucidating the role that miR147 occupies in modulating LPS induced cellular activation, and delineating the mechanisms through which miR147 affects LPS induced cellular activation. 2) To explore if modulation of the expression of miR147 attenuates LPS induced ALI by determining the expression of miR147 in the lungs of LPS treated mice and exploring if modulation of miR147 expression can attenuate LPS induced ALI. The proposed studies should not only improve understanding of cellular mechanisms leading to ALI, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of ALI. PUBLIC HEALTH RELEVANCE: MicroRNAs are important regulators of many essential cellular and developmental events. Deregulations of microRNA expression have been shown to be involved in a number of diseases, such as cancer, cardiovascular diseases, and diabetes. However, whether microRNAs regulate acute inflammatory responses and acute inflammation related diseases, including acute lung injury (ALI) has not been elucidated. We found that the expression of miR147 is upregulated in LPS stimulated macrophages and mouse lungs and miR147 has anti-inflammatory activities. The studies proposed in this application should not only improve understanding of the roles of microRNAs in regulation of LPS induced inflammatory responses and acute lung injury, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of acute lung injury.