Neutrophilic inflammation drives the immunopathology involved in numerous human diseases, including those directly involving an immune component such as rheumatic arthritis and those that are not obviously linked, such as diabetes, neurodegenerative disease and cancer. Recent evidences suggest that neutrophils are long lived cells that disseminate inflammation, critically regulate the magnitude of the inflammation and that bridge innate and adaptive immunities in both sterile inflammation and infection. Thus, a successful strategy to prevent the initial infiltration of neutrophils is expected to significantly improve inflammatory conditions and reduce the risk of many modern diseases. Neutrophil motility is targeted in clinical settings to treat inflammatory diseases such as gout and pericarditis. However, current drugs such as corticosteroids and the microtubule destabilizing agent colchicine lack neutrophil specificity thus are inevitably accompanied with adverse side effects. There is an urgent need to improve the existing regimes, which is dependent on a better understanding of the neutrophil-intrinsic mechanisms that specifically regulate neutrophil migration. MicroRNAs are evolutionarily conserved, small non-coding RNAs that post-transcriptionally regulate protein synthesis . MicroRNAs and anti-MicroRNAs have recently become strategies for treating human diseases. Although a list of microRNAs are identified in human neutrophils, their contributions in neutrophil migration as individuals or as a group have not been addressed. The absence of such knowledge creates a missed opportunity to harness microRNAs as tools in the prevention and treatment of inflammatory conditions. Here we propose the first systemic survey of the function of microRNAs in regulating neutrophil migration, aiming to identify and characterize microRNAs and anti-microRNAs with therapeutic potentials in restraining neutrophilic inflammation. We will #1. Determine how microRNAs collectively regulate neutrophil migration. #2. Screen for individual microRNAs that suppress neutrophil migration. #3. Determine how individual miRNAs suppress neutrophil migration. #4. Develop a tool to isolate neutrophil specific miRISC. Our work used zebrafish, a vertebrate model organism that allow for screenings of neutrophil intrinsic microRNAs for their contribution in regulating neutrophil migration, from the hematopoietic tissue to a localized infection, which is not possible in cell culture or in mice. To translate our findings to a more human health relevance setting, we will confirm our findings in human neutrophil like cells and inflammatory mouse models. Our preliminary studies strongly suggest that we have collected all the essential tools and identified candidate microRNAs to push this field forward significantly. Our contribution will be significant because it is expected to have broad translational importance in the prevention and treatment of a wide range of inflammation related disease.
Neutrophil migration and infiltration into tissue is associated with many chronic human conditions and diseases, such as allergies, atherosclerosis, cancer, arthritis, autoimmune diseases, neurodegenerative disorders, and others. The goal of the proposed research is to identify microRNAs and related signaling mechanisms that regulate neutrophil migration, from the hematopoietic tissue to a local inflammatory site, and ultimately lead to novel and much needed microRNA based therapeutics in treating those upper mentioned diseases.
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