Understanding Human Disease using Structural and Chemical Biology
Visiting Professor, SGC, Nuffield Department of Medicine; and Visiting Fellow, Magdalen College; Oxford University, 2013-2014. University of Washington, Seattle; Postdoctoral Fellow, 1995-1999. University of California, Los Angeles; Ph.D., 1995. University of California, Davis; B.S., 1990
Fellow, AAAS, 2013; Academic Leadership Fellow, UNC, 2011; Phillip and Ruth Hettleman Prize for Artistic and Scholarly Achievement, 2004; Burroughs Wellcome Career Award in the Biomedical Sciences 1999
Discovery Blocks Cancer Drug's Toxic Side Effect
Findings published in Science from the Redinbo Group, in collaboration with UNC School of Medicine, the Albert Einstein College of Medicine, and North Carolina Central University, may lead to the elimination of a debilitating side effect of CPT-11, a widely used but harshly potent treatment for colon cancer. The team of researchers, led by chemistry professor Matthew Redinbo from the University of North Carolina at Chapel Hill, has discovered that it is possible to target and block the enzyme, beta glucuronidase, which is thought to play a major role in causing the drug's side effects. "In a manner of speaking, we cured the bacteria's sweet tooth without damaging the microbes or intestines and, in the process, the drug's toxic side effect was alleviated," said Redinbo.
Study co-author, Sridhar Mani, professor of medicine and genetics at Einstein, said the severe diarrhea caused by CPT-11 can sharply limit the dosage that cancer patients can receive. "Our tests showed conclusively that the inhibitor identified by our UNC colleagues prevented diarrhea in mice that were also receiving CPT-11. We are hopeful that clinical trials will show that administering this inhibitor when patients start taking CPT-11 allows for improvement in the drug's anti-tumor effect in patients with cancer."
Cystic Fibrosis ResearchIn work published in PNAS, the Redinbo Group, in collaboration with the Tarran Group at UNC's Cystic Fibrosis Center, contributed the first crystal structure of SPLUNC1, the most abundantly secreted protein in human lungs. The structure lead the team to make specific electrostatic predictions regarding the surface of the SPLUNC1 protein, which were shown to be correct with respect to how SPLUNC1 controls the proper level of fluid in the lungs.
Cystic fibrosis, CF, is caused by mutations in the cystic fibrosis transmembrane conductance regulator, CFTR, gene, which codes for a chloride/bicarbonate channel whose absence leads to dehydration and acidification of CF airways. A contributing factor to CF lung disease is dysregulation of the epithelial Na+ channel, ENaC, which exacerbates mucus dehydration.
In the image above, healthy lung cells are on the right. The finger-like cilia point up into the proper fluid level because the blue SPLUNC1 proteins are "plugging" the ENaC channels (orange) which otherwise would remove Na (yellow) along with a lot of water. In CF lungs, left, the pH of the liquid is low, SPLUNC1 cannot bind to ENaC and plug that drain, so the Na and water flow into the cells, and the lungs become dehydrated. This work suggests that future CF therapy be directed toward raising the pH of CF airways.