Post-transcriptional Regulation of Gene Expression in Inflammation, Hepatotoxicity, and Cancer 

Innate immunity is a highly conserved response that quickly detects and attempts to clear pathogens and harmful environmental stimuli by inducing inflammatory responses. These responses are orchestrated via temporal and highly coordinated regulation of a number of genes. In addition to regulation at the transcriptional level, a majority of these genes are also regulated by post-transcriptional mechanisms that modify mRNA stability and/or translation. 

The goal of Dr. Patial’s research program is to understand the role of RNA Binding Proteins of the Tristetraprolin family in Health and Disease. Zinc finger protein 36 (ZFP36), also commonly referred to as Tristetraprolin (TTP), and the two other members of this family, Zinc Finger Protein 36 Like 1 (ZFP36L1), and Zinc Finger Protein 36 Like 2 (ZFP36L2) bind to AU-rich elements within the 3’untranslated regions of target mRNAs and result in their rapid turnover. TTP is known to regulate mRNAs of inflammatory mediators, including cytokines and chemokines. In this way, TTP regulates inflammation and innate immune responses.

We are particularly interested in understanding the role of TTP in direct and indirect Acute Lung Injury and Acute Respiratory Distress Syndrome (ALI/ARDS). In this context, we recently found that TTP modulates acute lung injury in mice and that TTP overexpression in non-hematopoietic cells protects against LPS-induced acute lung injury in mice. We are on our way to further explore whether this also holds true in terms of indirect acute lung injury and whether we can modulate TTP expression for protection against indirect acute lung injury. We are also investigating the cell-specific roles of TTP in lung disease.

Model showing role of TTP in endotoxin-induced acute lung injury: LPS/endotoxin damages epithelial cells within the lung which then initiates a cascade of events leading to exaggerated release of pro-inflammatory mediators and neutrophilic chemoattractants, resulting in neutrophilic infiltration and lung damage. In this process, TTP acts as an intracellular regulator for the expression of pro-inflammatory mediators and neutrophilic chemoattractants and thus confers protection against endotoxin-induced acute lung injury.

Mechanistic Role of TTP, ZFP36L1, and ZFP36L2 in liver inflammation and fibrosis

While much is known about the role of TTP in inflammation, the physiological and pathological roles of ZFP36L1 and ZFP36L2 remain elusive. However, our preliminary results show that both ZFP36L1 and ZFP36L2 play a critical role in regulating liver homeostasis and the liver’s response to environmental and occupational toxicants. Therefore, our second goal is to elucidate the molecular mechanisms of TTP family RNA binding Protein mediated regulation of liver inflammation and fibrosis.

The ultimate goal of our research is to gain mechanistic insights into the molecular mechanisms of lung and liver disease with the possibility of identifying novel diagnostic and prognostic biomarkers and to develop agents for prevention and therapy.