[olsen]

(thought appropriate, relating to the post concerning Brin's genetic mining. though study only in mice thus far, with mouse genetic mutations)

Gene + virus + injury = disease?


One of the most detailed studies to date of how the interaction between genes and environment results in disease has demonstrated that an inflammatory bowel disease resembling human Crohn's needs a specific mutation, virus, and injury to develop in mice.



"Environmental genomic issues are tough to crack," said John Mordes, professor of endocrinology at the University of Massachusetts, who has previously characterized a gene-virus interaction in type1 diabetes. "This is a significant contribution to the evolving understanding of how the environment interacts with genomic predisposition."

The team..., found that the diseased state was brought about by the complex interplay among a mutation in an autophagy-related gene called ATG16L1, a specific virus, a toxic substance, microbes in the rodent's gut, and the rodent's own immune response...

"It's a well-documented scientific example of how very particular environmental events and genes interact to result in disease," said Richard Blumberg,..
The researchers... [discovered] how a mutation in mouse ATG16L1 wreaked havoc in a type of cell that inhabits the lining of the small intestine. These so-called Paneth cells are involved in mucosal immunity and secrete antimicrobial proteins. But in mice that carry the mutation, the cells grow abnormally and malfunction, similar to what's observed in human Crohn's patients with mutations in the same gene.

But then, in early 2009, the mutant mouse colonies with the abnormal Paneth cells were moved to a new super-sterile facility. To the researchers' surprise, the mutant mice that grew up in the new facility had normal-looking, healthy Paneth cells. It was as if the mice didn't carry the mutation at all. This led them to believe that something other than genetics was at play.

Enter the murine norovirus -- a family of small, RNA viruses discovered by Virgin in 2003. The viruses are practically found in almost all mouse facilities except the new one, which was designed expressly to keep them out.

...when the researchers fed mutant mice different viral strains, they found that after exposure to one strain known as CR6, the Paneth cells transformed from healthy to abnormal.

... doctors have observed for years. "It is not uncommon to find that inflammatory bowel disease follows some sort of gastric infection in a clinical setting," Stappenbeck explained. ...

... when exposed to CR6 norovirus, the same set of genes that are down-regulated in normal mice are up-regulated in the mutant mice. As a result, in mutants, the Paneth cells are unable to secrete antimicrobial proteins -- leaving the microbe population in the gut unchecked.

In this perturbed state, an additional disruption of the intestinal tract could result in chaos. This is precisely what happened when the mutant mice with the viral infection were fed the toxic chemical, dextran sodium sulfate. This additional "environmental hit," which basically pokes holes into the intestinal lining, set off a cascade of events that resulted in a full-blown inflammatory bowel disease that displayed many of the hallmarks of human Crohn's disease.

"So really there were three environmental factors that were working together with the mutation: the viral infection, the composition of the microbiota (presumably induced by the viral infection), and a very specific inflammatory hit on the [intestinal lining]," Blumberg said.

...[researchers]found that by treating the mice with a wide spectrum of antibiotics -- in effect killing the intestinal microbes -- the disease state was eliminated.

... "Normally viruses aren't susceptible to antibiotics, but because this [disease], which is triggered by a virus, requires the presence of normal microbes in the gut, you can stop it by wiping them out."

The next step, Stappenbeck said, is to determine if there are human viruses that can trigger Crohn's. If so, it would explain why 50 percent of people with European ancestry carry the faulty ATG16L1 gene, but only a small fraction are affected. It might also explain why sometimes animal models carrying human susceptibility genes, but without their triggers, don't develop the disease.

The paper "sort of opens a Pandora's box that makes interrogating the gene-environment interactions in this and other complex diseases much more complex," Blumberg said.


Read more: Gene + virus + injury = disease? - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/di...#ixzz0ro14K3Au

[paula_w]

seems we've heard this story a few times over the years haven't we? science is trying to catch up and seems open to more ideas.. knock wood.

the combinations of insults are endless. does anyone know anything about laminin? it is talked about in the christian world because it is suppposed to "hold everything together" like glue and is shaped like a cross.

we are coming unglued in every way
wondering what role laminin plays, if any, to neurodegeneration.

excellent find madelyn
paula

[RLSmi]

Originally Posted by paula_w

seems we've heard this story a few times over the years haven't we? science is trying to catch up and seems open to more ideas.. knock wood.

the combinations of insults are endless. does anyone know anything about laminin? it is talked about in the christian world because it is suppposed to "hold everything together" like glue and is shaped like a cross.

we are coming unglued in every way
wondering what role laminin plays, if any, to neurodegeneration.

excellent find madelyn
paula

Paula, laminin is an important protein componenet of the extracellular matrix (ECM) one type of connective tissue. Bone and cartilage are two others. ECM surrounds and "connects" all of the other cells of the body. The main ECM proteins are collagen, fibronectin and laminin. Laminin is especially prevelent in basement membrane, a particular form of ECM.

When laminin is isolated from ECM and veiwed in the electron microscope, it has what is referred to as a "cruciform" shape; that is, its different polypeptide (protein) chains assemble to form a cross.

I have seen videos of a Christian preacher using the electron micrograph of a laminin molecule to enhance his evangelical message. I assume this is what you are referring to.

Robert

[paula_w]

It sounds like it isn't neurodegenerative and I do realize there is nothing to scientifically connect religion and science about its' shape - just wondered.