We study neutrophil migration and the inflammation process using the zebrafish model. We are also interested in establishing novel infection models using zebrafish where pathogene-host interactions are made transparent. Currently we have 4 major projects in the lab.
Project #1: Identification and characterization of micro-RNAs that moderate acute neutrophilic inflammation
Using next generation sequencing, we have identified miRNAs that are enriched in neutrophils. We have finished a targeted screen and identified miRNAs that suppress neutrophil migration. The immediate goal will be to characterize the contribution of each individual miRNA in regulating neutrophil motility and their impact on the outcome during infections.
Project #2: MiR-223 and neutrophilic inflammation
MicroRNA-223 is known as a myeloid-enriched anti-inflammatory microRNA that is dysregulated in numerous inflammatory conditions. We find that neutrophilic inflammation (wound response) is augmented in miR-223-deficient zebrafish, due primarily to elevated activation of the canonical NF-κB pathway in epithelial cells, and this direct connection between miR-223 and the canonical NF-κB pathway provides a mechanistic understanding of the multifaceted role of miR-223 and highlights an overlooked relevance of epithelial cells in dampening neutrophil activation.
Project #3: Mitochondria and neutrophil migration
Neutrophils are fast moving cells essential for host immune functions, and they primarily rely on glycolysis for ATP. Whether mitochondria regulate neutrophil motility in vivo, however, and the underlying molecular mechanisms remain obscure. To dissect mitochondrial function genetically, we establish a system harboring the CRISPR/Cas9 elements for tissue-specific knockout. With this system, we provide the first in vivo evidence that mitochondria regulate neutrophil motility, tools for the functional characterization of mitochondria related genes in neutrophils, and insights into immune deficiency seen in patients with primary mitochondrial disorders.
Project #4 Neutrophil response in ZIKV infection
ZIKV is a member of the Flaviviradae virus family and is mainly transmitted by daytime-active Aedes mosquitos. The danger of ZIKV on pregnancy is a public health emergency of global concern. An irreversible severe brain malformation, microcephaly, and other birth defects are seen in babies born to infected woman. Despite efforts to eradicate the mosquito carriers and to develop a vaccine to control the spreading of the disease, the pathogenesis of ZIKV in the infected fetus is poorly understood. Viral-host interaction in the developing fetus and neonates is different from that in adults, when the adaptive immunity is maturing and not fully functional. Neutrophils are the first line of defense against infections, and are especially important in the babies. On the other hand, neutrophilic inflammation drives the immunopathology of numerous human diseases, including infections. The goal here is to characterize the role of neutrophils in ZIKV-infected embryos, which can inform the design of the much needed therapeutics that fine tune and moderate neutrophilic inflammation and restore the normal development of the infected fetus.