February 13, 2004
Phone: (504) 865-5714
As a pediatric nephrologist, Samir El-Dahr treats babies born without kidney function who must start dialysis the very first day of their lives.
So, as a researcher, his work to suss out the intricate process of terminal differentiation in the kidneys is much more than an academic exercise. Terminal differentiation is the last stage of kidney development.
In humans, it takes place before birth in the third trimester. The kidneys are formed but the filtering units, called nephrons, are still immature and dividing. And then somehow they get genetic instructions to stop dividing and start functioning.
But if the genes that mediate terminal differentiation are not expressed in the right place or at the right time, the instructions get garbled and the kidneys won't function.
"We are very interested in this process," said El-Dahr, professor of pediatric nephrology. "We think there's a master genetic program." His lab, including assistant professor Ihor Yosypiv and National Institutes for Health, supported postdoctoral fellow Zubaida Saifudeen, is responsible for groundbreaking research in kidney development. They recently received a $1 million grant from the NIH to extend their research.
They began by studying the receptor for a hormone called bradykinin, which regulates how much salt and water is absorbed by the nephrons. The receptor is only present on nephrons that have reached terminal differentiation. Working with mice, researchers found that if they interfered with the receptor, either through drugs or by breeding animals that had the gene for the receptor knocked out, they would end up with kidneys that failed to enter terminal differentiation and animals that were salt-sensitive and developed high blood pressure. Researchers then began looking at the transcription factors that regulate the gene.
Transcription factors are proteins that dictate to a gene what it should do. They found that a particular transcription factor, p53, regulates the bradykinin receptor in addition to other genes involved in terminal differentiation. p53 was known to be a tumor suppressor--mutations in the p53 gene are found in more than half of all human cancers. El-Dahr found that mice that lacked p53 not only developed cancer, but also had malformed kidneys.
"In some models we eliminated p53 completely and in others we left it in but eliminated its ability to bind the DNA," El-Dahr said. "The more we look into this, the more we find that p53 is not the end of the line. Other factors are working with it. It's a very complex process."
Their new grant will allow them to study the regulation of p53 and identify target genes downstream of p53, which mediate terminal differentiation in normal kidneys. The better they can understand kidney development, the better they will be able to monitor the process and correct problems in utero.
"Our hope is to be able to do a genetic test to detect specific genetic mutations and fix them before the baby is born," El-Dahr said. "We might administer growth factors to heal the kidney or manipulate the gene pharmacologically."
Eventually, a better understanding of kidney development should lead to the ability to heal adult kidneys that have failed. It could also help to better understand the development of other organs.
"Most organs seem to develop in the same way, with the same signaling process, just with different transcription factors. The same general principles apply. So if you have a great success with one organ, it could help us understand the development of another organ."
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