Role of Biological Sex on Non-Alcoholic Fatty Liver Disease Progression to Hepatocellular Carcinoma
Standing
Undergraduate
Type of Proposal
Oral Research Presentation
Challenges Theme
Open Challenge
Faculty Sponsor
Dr. Lisa Porter & Dr. Bre-Anne Fifield
Proposal
Hepatocellular carcinoma (HCC) is the most prevalent primary cancer of the liver and one of the leading causes of cancer-related deaths worldwide. Men are almost 3x more likely to develop HCC; however, the exact mechanism for this remains undetermined. Non-alcoholic fatty liver disease (NAFLD) is a major risk factor for HCC. Hepatocytes are typically held in a state of quiescence, however, in response to this chronic injury, they can rapidly reenter the cell-cycle to respond to damage and restore functional mass in the liver. Quiescence and Reentry into the cell-cycle is tightly controlled by the activity of cyclin dependent kinases (CDKs). Sex-specific differences with respect to physiology have been suggested to play a major role in response to hepatic injury; however, they have yet to be explored in cell-cycle regulation and exit from quiescence. Spy1, an atypical cyclin like protein, can bind and activate CDK1 and CDK2, and override cell-cycle checkpoints and quiescent barriers. Thus, Spy1 may be an important mediator of hepatocyte exit from quiescence in response to injury and may account for sex-specific differences in cell-cycle reentry. To better understand hepatic regenerative processes, the methionine choline deficient (MCD) diet, an excellent inducer of NAFLD will be administered to wildtype, male and female mice. Morphological and cell-cycle profile differences will be investigated to quantify the livers regenerative state in wildtype mice. This project will uncover Spy1’s role in sex-specific hepatic regeneration and will identify novel diagnostic markers and pathways of therapeutic importance in HCC.
Grand Challenges
Viable, Healthy and Safe Communities
Role of Biological Sex on Non-Alcoholic Fatty Liver Disease Progression to Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most prevalent primary cancer of the liver and one of the leading causes of cancer-related deaths worldwide. Men are almost 3x more likely to develop HCC; however, the exact mechanism for this remains undetermined. Non-alcoholic fatty liver disease (NAFLD) is a major risk factor for HCC. Hepatocytes are typically held in a state of quiescence, however, in response to this chronic injury, they can rapidly reenter the cell-cycle to respond to damage and restore functional mass in the liver. Quiescence and Reentry into the cell-cycle is tightly controlled by the activity of cyclin dependent kinases (CDKs). Sex-specific differences with respect to physiology have been suggested to play a major role in response to hepatic injury; however, they have yet to be explored in cell-cycle regulation and exit from quiescence. Spy1, an atypical cyclin like protein, can bind and activate CDK1 and CDK2, and override cell-cycle checkpoints and quiescent barriers. Thus, Spy1 may be an important mediator of hepatocyte exit from quiescence in response to injury and may account for sex-specific differences in cell-cycle reentry. To better understand hepatic regenerative processes, the methionine choline deficient (MCD) diet, an excellent inducer of NAFLD will be administered to wildtype, male and female mice. Morphological and cell-cycle profile differences will be investigated to quantify the livers regenerative state in wildtype mice. This project will uncover Spy1’s role in sex-specific hepatic regeneration and will identify novel diagnostic markers and pathways of therapeutic importance in HCC.