Lung infections represent a significant burden of disease worldwide and are a common cause of acute lung injury. The pulmonary immune response during bacterial pneumonia is a tightly regulated process that eliminates bacteria while preventing host tissue damage due to excessive inflammation. To orchestrate this delicate balance, host inflammatory cytokine production must be dynamically regulated by both transcriptional and post-transcriptional mechanisms of gene expression. MicroRNA (miRNA) is emerging as an important class of post-transcriptional regulators of multiple cellular processes including inflammation. Recent studies utilizing deep-sequencing of small RNAs have revealed a tremendous amount of sequence diversity of miRNA, however, the functional significance of these sequence variations is unknown. One enzyme known to contribute to miRNA diversity is Zcchc11, a uridyltransferase enzyme that adds uridines to the ends of specific miRNAs. In addition to miRNA editing, our preliminary data show that Zcchc11 regulates cytokine expression, thus suggesting that Zcchc11- mediated miRNA sequence modifications could play a significant role in the post- transcriptional control of cytokine production. We will pursue 3 aims to test the central hypothesis that Zcchc11 uridylates mature miRNAs during pneumonia to regulate cytokine expression and lung inflammation. 1) Test the hypothesis that cytokine- targeting miRNAs are uridylated by Zcchc11 during inflammatory conditions. 2) Test whether sequence elements within uridylated miRNAs and target mRNAs are required for Zcchc11-dependent cytokine expression. 3) Test the hypothesis that Zcchc11- regulated cytokines are essential determinants of the host defense and lung injury during pneumonia. The knowledge obtained from the studies performed in this proposal will be of biological significance for identifying novel molecular mechanisms of gene regulation, miRNA uridylation by Zcchc11, to alleviate the silencing of target mRNAs. Insights obtained from these studies may also be medically significant in that a better understanding of how miRNA editing impacts the host response during pneumonia may lead to new avenues for diagnosis and prevention.
Pneumonia is a major public health problem worldwide that urgently needs to be addressed. Our research is focused on understanding how the strength of the host immune response to pneumonia is balanced to eliminate bacteria while avoiding excessive lung damage. These results of these studies may help in the rational design of pharmacologic therapeutics that target novel mechanisms involved in regulating the immune response during infection.
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