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Approved Research

Genetics of Hyperceramidemia

Principal Investigator: Professor Scott Summers
Approved Research ID: 73856
Approval date: March 30th 2023

Lay summary

Michael Brown and Joseph Goldstein, who were awarded the Nobel Prize for their exquisite work on the molecular mechanisms surrounding cholesterol metabolism, embarked on their paradigm-shifting journey because of encounters with children with familial hypercholesterolemia. A key feature of their work was an analysis of genetic mutations that led to profound increases in serum cholesterol and frequent heart attacks. Through this analysis, they determined that mutations in a low-density lipoprotein receptor caused hypercholesterolemia and cardiovascular disease. Building on these discoveries, they determined the mechanisms that controlled lipoprotein production, a tour de force that established several new paradigms in biology and medicine. Of course, the work ushered in the development of statins, one of the most efficacious and widely prescribed classes of drugs.

We propose to conduct a similar analysis of ceramides, which are products of protein and fat metabolism that accumulate in people that are obese. Ceramides can damage cells and tissues, and appear to play causal roles in a number of insidious pathologies, including diabetes and heart disease. Indeed, clinics now measure serum ceramides as indices of disease risk. Using the rich and distinctive tools present in the UB Biobank, we will try to identify individuals with a genetic predisposition to accumulate ceramides and suffer from their damaging effects. Such information could have important implications: (i) defining causal roles for ceramides in cardiometabolic pathologies; (ii) revealing regulatory networks that influence ceramide synthesis, metabolism, or trafficking; and (iii) ultimately supporting development of personalized interventions to lower ceramides and treat disease.