**6. Opportunity and potential impact**

Numerous markers of oxidative stress and antioxidant status have been evaluated, but there has been little systematic effort to validate sensitive and specific biomarkers for oxidative damage in animal models.

Development of miRNA as a new biomarker for alcohol-induced oxidative stress is limited by the lack of easy access to the tissues from patient populations. Therefore, the majority of discovery work will need to be carried out in the animal model of ALD. The advantage provided by animal models is the ability to control and define disease stages. We have to correlate these model diseases to the clinical status of actual patient populations. The process of biomarker discovery in animal models will be validated by clinical studies. As the technology develops to allow higher throughput screening of miRNA, these candidate biomarkers can be more easily tested and applied to larger patient populations.

The *long term goal* of our laboratory is to design an effective therapeutic intervention to prevent and treat oxidant-induced disorders. Increasing our understanding of the mechanism of oxidant-induced gut leakiness should lead to identification of optimal targets for development of new preventive and therapeutic strategies for alcohol-induced, endotoxin mediated, tissue damage such as ALD. Our studies should thus lead to development of: **a)** miRNA as biomarkers for identifying susceptible individuals who are at risk for endotoxemia & ALD and would thus benefit from interventions that prevent gut leak; **b)** novel strategies to prevent ALD by preventing gut leakiness and endotoxemia in alcoholics; **c)** novel therapies to treat advanced alcoholic and non-alcoholic liver disease, because gut leakiness can perpetuate the hepatic necroinflammatory cascade (via feedback loops) and thereby contribute to the progression of liver injury. Since our model involves oxidative stress and iNOS, the results could have relevance to other pathological conditions where gut leakiness and oxidative stress play key roles like non-alcoholic liver disease, inflammatory bowel disease & food allergy to name a few.
