Hepatocellular cancer (HCC) is the fastest increasing cause of cancer-related death in the United States. Texas has the highest incidence and mortality rates for HCC in the nation. Multiple risk factors are enriched in nearly half of all Texans, particularly obesity and non-alcoholic fatty liver disease (NAFLD), which could have a causative influence on HCC incidence. However, we do not understand how obesity and NAFLD drive the progression of HCC, and we lack curative solutions to halt the combined effects of these chronic diseases.

My research will define the mechanistic impacts of circadian misalignment on fatty liver progression. Circadian misalignment among obese individuals is increasi...

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Hepatocellular cancer (HCC) is the fastest increasing cause of cancer-related death in the United States. Texas has the highest incidence and mortality rates for HCC in the nation. Multiple risk factors are enriched in nearly half of all Texans, particularly obesity and non-alcoholic fatty liver disease (NAFLD), which could have a causative influence on HCC incidence. However, we do not understand how obesity and NAFLD drive the progression of HCC, and we lack curative solutions to halt the combined effects of these chronic diseases.

My research will define the mechanistic impacts of circadian misalignment on fatty liver progression. Circadian misalignment among obese individuals is increasingly being recognized as a risk factor for NAFLD and HCC due, in part, to the dissonance between the body’s endogenous timing and bombardment with light and food throughout the day. I showed that obesity and NAFLD cause non-canonical clock regulators to engage in rhythmic regulation of lipid metabolism and fatty liver progression.

The objective of this proposal is to examine the role of non-canonical clock regulators in obesity-related HCC. Specifically, I will use state-of-art genome-wide approaches to identify how dietary interventions that cause obesity and fatty liver diseases alter non-canonical clock regulators, leading to HCC. My laboratory will use cutting-edge unbiased genome-wide enhancer analysis, newly established in vivo CRISPR/Cas9 screening methods, and gene expression profiles in human liver cancer tissues to explore how these non-canonical clock regulators affect fatty liver progression to HCC.

In summary, the proposed research will uncover HCC development mechanisms, which can be used as a basis for therapeutic strategies to reduce the incidence and mortality of HCC.

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