Researchers Find Cause of Liver Cirrhosis, Develop Treatment That Blocks It

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Researchers Find Cause of Liver Cirrhosis, Develop

Treatment That Blocks It

LA JOLLA, Calif., Oct. 25 (AScribe News) --

Researchers in San Diego and the United Kingdom have

identified a protein segment and the mechanism that

underlies excess fibrous tissue growth leading to

conditions such as liver fibrosis and cirrhosis. In

addition, they've developed a mutated version of the

protein that blocks this excess scar tissue in mice.

The study is published in the Oct. 26, 2001 edition of

the journal Molecular Cell by researchers at the

University of California, San Diego (UCSD) School of

Medicine, the VA San Diego Healthcare System, the Salk

Institute for Biological Studies, and the University

of Dundee, United Kingdom.

Lead author a Buck, Ph.D., a UCSD and VA

research scientist, found that a small piece of an

important regulatory protein called C/EBP beta was

responsible for fibrous tissue growth - which is

excessive scar tissue - following injury or chronic

illness. An appropriate amount of fibrous tissue

growth is valuable, such as the formation of a scar

over a skin wound. When normal healing goes awry,

however, excessive build up of fibrous tissue can

produce disfiguring scars externally or clog vital

internal organ functions and lead to serious

complications. By isolating a small section of C/EBP

beta and changing one of its molecular components -

amino acids, the building blocks of proteins - Buck

and her team developed a mutated protein that stopped

excessive fibrous tissue growth.

Although the study focused on liver injury in mice,

the findings may also apply to fibrous tissue growth

in other organs, such as the kidneys, lungs and skin,

said the study's senior author Chojkier, M.D.,

UCSD professor of medicine and a liver specialist at

the VA Medical Center.

" In some individuals, " he added, " injury or a chronic

illness causes fibrous tissue to accumulate. In

severely burned patients, there could be terrible skin

scarring. In the liver, this can lead to cirrhosis and

serious, life threatening medical complications such

as internal bleeding, fluid accumulation, and an

inability to handle medications or environmental

toxins. However, until now we haven't known how this

process occurred at the molecular level and how we

might prevent it. "

The researchers' discoveries began with an

investigation of the known events leading to excess

tissue growth. With liver injury or a chronic illness

such as viral hepatitis, a molecular chain of events

leads to stimulation of specific liver cells called

stellate cells, causing them to grow in number and

size, producing the excessive amounts of fibrous

tissue that interferes with normal function.

The team determined that injury or chronic illness

activates a phosphorus molecule which attaches to an

amino acid sequence within the C/EBP beta protein. The

centerpoint for the team's study became that amino

acid sequence, KTVD, which consists of lysine (K),

threonine (T), valine (V) and aspartic acid (D). With

phosphorylation of KTVD - the addition of a phosphorus

molecule - the amino acid sequence blocked the normal

activity of another group of enzymes called caspases,

which ordinarily would prevent the overproduction of

fibrous tissue, resulting in excessive scar tissue

growth.

To block the development of excess fibrous tissue, the

researchers bred mice with KAVD, a modified version of

the amino acid sequence that substituted an amino acid

called alanine (A) for threonine (T). With this

mutated amino acid sequence, the mice responded

normally to liver injury and damage, without excessive

scar tissue build up. Specifically, KAVD blocked the

phosphorylation that had occurred with the KTVD amino

acid sequence and allowed normal activation of caspases.

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