Gerald Hart, Ph.D.

Drug Discovery
The University of Georgia
Recruited: 2018

Gerald Hart’s research is devoted to answering a fascinating question: what role do sugar molecules play in the secret language of cells?

When a sugar molecule attaches itself to a protein, big things happen: changes in shape, structure, function. When these protein changes occur inside a cell, they can have big implications.

In the 1980s, Hart was the first to discover the sugar-protein modification could happen in the inner part of a cell, the cytoplasm or the nucleus. In the decades since, he and scientists around the world have leveraged this knowledge to explore the impacts on human health.

Here’s a breakdown of his discovery:

  • When a sugar molecule modifies a protein molecule’s shape and function, it’s called glycosylation. This change process has long been known, but it was believed to occur only in outer compartments of the cell.
     
  • Hart’s breakthrough discovery came when he found that glycosylation also frequently occurs inside the nucleus and cytoplasm of cells. This type of glycosylation is called O-linked N-acetylglucosamine, or O-GlcNAc for short.
     
  • As researchers are discovering, O-GlcNAc seems to play a role in nearly every cell function, particularly cell signaling and transcription (which uses genetic information to make proteins). O-GlcNAc is connected to diseases such as diabetes, cancer and Alzheimer’s.
     
  • Hart compares this sugar cycling to a dial that controls processes in the cell, modulating them up or down depending on a host of factors, such as the amount of available nutrients.
     
  • One example can be found in diabetes. When glucose gets too high, O-GlcNAc also gets too high, and the sugar levels in the cell stay up. This affects cell transcription and signaling, activating genes that cause symptoms such as insulin resistance.

Because the field is so new — and has such broad implications — the possibilities for study are enormous. One of the biggest challenges is simply choosing which aspect of O-GlcNAc’s impact to unravel next.

So far, they’ve found that increased O-GlcNAc contributes to diabetic cardiomyopathy, a condition that causes heart failure in patients with diabetes. They’ve also connected a decrease in O-GlcNAc to Alzheimer’s disease and other neurodegenerative diseases. And alterations in O-GlcNAcylation are now linked in numerous, complex ways to the biology of cancer.

These and other discoveries would not have been possible without Hart’s foundational work.

For now, Hart’s lab is primarily focused on deepening an understanding of the role O-GlcNAc plays in Alzheimer’s and diabetes. Other labs are building on Hart’s early work to explore O-GlcNAc’s impact on cancer, heart problems, aging and more.

In diabetes, for example, Hart’s team is investigating how O-GlcNAc is part of a mechanism controlling kidney function. In particular, they’re looking at two proteins that help the kidney fulfill its function of filtering toxins. In diabetic patients, sugar is high, and so is O-GlcNAc. This sugar cycling in the cell shuts down the cell transcription process that enables those toxin-filtering proteins to keep creating themselves. By better understanding this mechanism, Hart’s lab could help pave the way for treatments that improve diabetic patients’ kidney function.

The University of Georgia is home to the Complex Carbohydrate Research Center, widely recognized as the world’s top organization for studying the science of sugar. In his role at UGA, Hart benefits from partnering with a world-class interdisciplinary group of carbohydrate scientists. And the center benefits from his expertise as one of the foremost leaders in the field. CCRC Director Alan Darvill calls Hart “a natural fit,” adding that he brings “some rather large interdisciplinary grants in glycobiology, and that’s something we couldn’t do without him.” 

 

Research

  • Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins
  • Cross talk between O-GlcNAcylation and phosphorylation
  • O-GlcNAc in diabetes and diabetic complications
  • O-GlcNAc and diabetic cardiomyopathy 
 

Straight from the Scholar

“The Complex Carbohydrate Research Center is the best place in the world for glyco research. I’ve been coming here since 1989. The people here are phenomenal, the quality is outstanding. And I no longer have an hour-long commute every day.” 

 



 Gerald  Hart, Ph.D.