The National Institutes of Health has awarded Wayne State University Assistant Professor Shengyi (Iris) Sun, Ph.D., a three-year, $1.18 million grant to investigate the role of endoplasmic reticulum-associated degradation in regulating the biogenesis of the liver protein fibrinogen, a key factor in bleeding disorders and liver diseases.

The study could advance understanding of conformational diseases associated with protein misfolding.

“Protein is one of the most important building blocks of our body. Our bodies are made up of thousands of different proteins, each with a specific function,” Dr. Sun said. “When we make the proteins, just like in a factory, mistakes happen and defective products need to be examined and eliminated. Our research investigates the mechanism mediating such protein quality control process, and how this mechanism is linked to various human diseases, for example, liver diseases.”

Dr. Sun is a principal investigator in the Center for Molecular Medicine and Genetics, and the Department of Biochemistry, Microbiology and Immunology.

“Novel mechanism underlying fibrinogen biogenesis in the endoplasmic reticulum,” is funded by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases.

“A large number of human diseases are now recognized as ‘conformational diseases,’ caused by protein misfolding and subsequent aggregation,” she said. “One example is hepatic fibrinogen storage disease, where the underlying cause is the endoplasmic reticulum, or ER retention and aggregation of fibrinogen mutants, leading to liver damage, hypofibrinogenemia and excessive bleeding. However, the molecular events underlying the biogenesis and quality control of both wildtype and mutant fibrinogen in the ER remain unknown.”

Fibrinogen is essential for hemostasis. Its aberrant biogenesis is directly linked to bleeding disorders and liver diseases.

“This application, with parallel physiological and biochemical studies, will establish a direct link between endoplasmic reticulum-associated degradation and fibrinogen biogenesis, uncover novel mechanisms underlying protein aggregation and inclusion bodies in the ER, and advance our understanding of disease pathogenesis and therapeutic approaches associated with protein misfolding and aggregation in general,” Dr. Sun said.

Her co-investigators are University of North Carolina at Chapel Hill scientist Matthew Flick, Ph.D., and Michigan State University scientist James Luyendyk, Ph.D.

The award number for this NIH grant is R01DK132068.