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New Insights Into Congenital Diaphragmatic Hernia

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New Insights Into Congenital Diaphragmatic Hernia

Mar 27, 2015

Congenital diaphragmatic hernia (CDH) is not as well known as muscular dystrophy and cystic fibrosis, but like them it is a life-threatening birth defect, and is just as common. Occurring in one in 3,000 births, CDH causes the guts and liver to protrude through a defective diaphragm and into the chest cavity, where they interfere with the lungs. A new study led by Gabrielle Kardon, Ph.D., associate professor of human genetics at the University of Utah is the first to demonstrate how genetic defects cause a physiological mechanism that gives rise to defects in the diaphragm. She describes her research and how it may lead to new approaches for therapeutic interventions. Learn more.

Episode Transcript

Interviewer: Research that gives us a new understanding of common yet relatively unknown birth defect, congenital diaphragmatic hernia.
Examining the latest research and telling you about the latest breakthroughs, The Science and Research show is on The Scope.
I'm talking with Dr. Gabrielle Kardon, Associate Professor in Human Genetics at the University of Utah. She's just published research in the journal Nature Genetics that gives us a new perspective into the causes of congenital diaphragmatic hernia or CDH. Dr. Kardon, I had not heard of CDH before can explain what that is?

Dr. Kardon: Most people are familiar with hernias as inguinal hernias and so in an inguinal hernia, you have a weakness in your abdominal wall and your guts basically protrude through your abdomen. And what you can think of CDH as an inguinal hernia in reverse. So instead of your guts going downwards they go upwards through to weakened diaphragm and up into the thoracic cavity and the big problem is if you have your liver and your guts into thoracic cavity, they will basically interfere with the growth of the lungs.

Interviewer: Before your research what did we know about how this birth defect happens?

Dr. Kardon: So I would say the majority of the information about CDH actually comes from human geneticist. They take blood samples from CDH patients and they look at the genetics and they look and see whether there are mutations in their genes or the regions of their chromosomes that are deleted. And so basically what we know is a whole lot of genes and quite a few chromosomal regions that are strongly correlated with the incidents of CDH. And the real problem has been that we have no idea how these mutations lead to CDH. And I think that's the problem that we were interested in addressing. How do we go from a mutation to developing a weakness in the diaphragm?

Interviewer: And that's part of why your research is so insightful because you came at it from a totally different approach than what's been done before?

Dr. Kardon: Right. So we just started by looking at how the diaphragm normally form and basically we looked at a lot of different kinds of mice where we could genetically label different components of the developing embryo to track where did the muscle cells come from, where does the connective tissue come from, where does the tendon come from and how they get linked up.

Interviewer: And that's part of your research too is understanding what happens normally and then understanding what happens in the context of CDH.

Dr. Kardon: Right.

Interviewer: So what do we know now about what happens normally and then what goes wrong?

Dr. Kardon: Basically the diaphragm you can think of as a ring of muscle cells and that inside the center of that ring the muscle cells are hooked up to tendons and surrounding each one of those muscle cells is a bunch of connective tissues or collagen. And that collagen is linking the muscle to the tendon and also the muscle to the bone.
And so normally we think of the connective tissue as basically providing structural support and holding the thing together, but basically playing a pretty passive role. And then the surprising thing that we found in development is that the connective tissue was the driving force for diaphragm development. It basically told all the other cells what to do.
And so we basically took our cue from the human genetics studies and we looked at basically one of the most prominent genes that has been identified as playing a role in CDH and this was a gene that's called GATA4. And what we used was some fancy tricks so we could knock out GATA4 and its function in particular cells.
And what we found that was really surprising is that GATA4 was essential in the connective tissue. Now when you got rid of GATA4 in the connective tissue you always got hernias and the hernias looked just like the patient hernias. And so we had weaknesses in the diaphragm. We had the liver herniating through the diaphragm and the mice had small lungs and just like the human patients most of those mice died at birth.

Interviewer: One thing that was amazing to me is that you got these hernias every time you did that experiment, which doesn't happen very often in science.

Dr. Kardon: Right. We have now looked at hundreds of these mice and every single time we knock out the gene in the connective tissue and I should point out not in the muscle. So in the connective tissue we have these hernias.

Interviewer: The way these hernias develop is actually little bit counterintuitive.

Dr. Kardon: Right, so there's just decades of data on hernias in patients and from that data, doctors had always suggested that hernias were holes in the diaphragm and that through these holes, the liver and the guts can herniate through. And what we found is that in the mice, where we can observe the formation of hernias from the very beginning, what we found is that there hernias are not initially holes in fact what they are, are regions of connective tissue but that have no muscle in them. And so they are not actually holes.
So the holes may form later as the liver keeps protruding through this region which is really weak and has no muscle but initially it doesn't start out as a hole. So that's completely counter with the dogma that is from the physicians and pediatric surgeons.

Interviewer: Now that you have all this basic information what can you do with that?

Dr. Kardon: So we know that the connective tissue is the problem and the other thing that was really surprisingly learned is that the defect is really early. So typically in humans a mother learns that her baby has CDH by an ultrasound at roughly 20 weeks. And this is quite late and in the mice, where they have a much shorter gestation time, we see herniation about two thirds of the way through gestation but when we look earlier we see that the defect is much, much, much earlier. In fact the defect would correspond to roughly between 40 and 60 days in utero in a human so it's much earlier.
But the idea is that we could actually go and test some potential therapies in our mouse embryos and see if we could rescue these mice, that we know will get hernias if we allow them to develop. And can we somehow intervene? So obviously clinical trials is a big deal and especially when you're talking about doing something potentially in utero. So you need to be able to try to test things in something other than a human. And the trick has been that we've never had basically a very good mouse model of CDH and so I think it's an excellent starting point that we haven't had before.

Interviewer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.