$1.2 Million Funds Study of Crucial Cellular Iron Management Process

The four-year project is funded through the National Institute of Diabetes and Digestive and Kidney Diseases.

“A multitude of human pathologies are often attributed in part to mismanaged ionic iron, particularly neurodegenerative disorders involving aggregation of brain proteins, including Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (Lou Gehrig’s disease),” Kosman says.

“This oft-cited role of iron in human pathology—from post-ischemic tissue damage to neurodegenerative disease—is testament to the importance of managing ionic iron,” Kosman notes.

“What we learn from this research will make a significant contribution to our eventual elucidation of the molecular basis for these diseases,” he adds.

Kosman and his collaborators will provide insight into how cells manage iron chemistry in order to balance essential, yet potentially harmful, processes.

This cellular balancing act involves suppressing the element’s inherent and potentially cytotoxic reactivity, while making it available as a co-factor for a multitude of critical cellular activities, including energy metabolism in the brain.

“In fulfilling their essential need for iron, aerobic organisms like fungi—and humans—have to rely on biochemical pathways designed to deal with the aqueous and redox chemistry of ionic iron,” Kosman explains.

“This chemistry renders iron nutritionally bio-unavailable, while making iron an oxidative threat,” he says. “Iron’s contribution to neurodegenerative disease is due to this chemistry.”

The researchers aim to determine the mechanism that allows iron to pass across the blood-brain barrier into hippocampal neurons.

Their projects will shed light on how various types of cells—capillary endothelial cells, astrocytes and neurons—manage iron chemistry in the brain.

This research builds on Kosman’s previous collaborative studies that have made major contributions to the understanding of the molecular and electronic bases for the unique reactivity of copper oxidases.

The new grant will allow the researchers to test the following:

• a model for how a reductase (reducing enzyme), permease (membrane transport protein) and ferroxidase (copper-containing enzyme) combine to support iron trafficking across the blood-brain barrier
• a hypothesis about the iron-trafficking pathway that combines two types of reactions (ferroxidase and permeation) as fungi, including human pathogens, acquire iron
  
• hypotheses about fundamental unknowns in eukaryotes’ handling of ionic iron