Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mouse research sheds new light on human genetic diseases

28.04.2003


A team of researchers headed by Douglas R. Cavener, professor and head of the Department of Biology at Penn State University, has announced important findings about the causes of three human diseases: severe, juvenile-onset diabetes; osteoporosis; and Wolcott-Rallison Syndrome, a rare condition whose sufferers exhibit a combination of diabetes, retarded growth, and skeletal abnormalities. Their work suggests promising lines of research for the therapeutic treatment of these diseases. The work will be described in an article in the August 2003 issue of the journal Endocrinology.


Three mice that are littermates (siblings of the same age). The two mice on the left (one partially hiding under the big mouse) are dwarf mice caused by the Perk mutation. They are less than half the size of the mouse on the right, which is normal.


Micro x-ray computed tomography (microCT) images of the tibia of normal and Perk mutant mice. The mutant shows thin cortical bone with deformations and gaping holes. "If it wasn’t for muscle and connective tissue to hold these fragile bones together, these mice would fall apart," Cavener says.



Over several years, Cavener’s team has developed and investigated a particular strain of "knockout" mice that are genetically unable to produce the enzyme PERK (pancreatic endoplasmic reticulum kinase). Cavener and his team hypothesize that the PERK enzyme is a specific or global regulator of protein synthesis, which means that the knockout mice are especially useful in unraveling complex physiological and developmental processes. "We are now able to investigate what happens when a particular gene is missing, to see what functions go wrong. Then we work backwards to fill in mechanisms that link the genotype to the phenotype" or the observable outcome, Cavener says.

PERK knockout mice have a very low survival rate because the biomedical problems caused by the absence of the PERK enzyme are so severe. Fully 63 percent die during gestation or the first few days of life which can be traced to failures in the creation or delivery of specific proteins.


The surviving PERK knockout mice have three distinct problems that parallel those seen in humans with Wolcott-Rallison Syndrome. First, the knockout mice grow very slowly so that, as adults, they are about half the size of normal mice. They are strikingly deficient in a factor which regulates growth known as IGF-1. Newborn knockout mice average only about 25% as much IGF-1 in their liver and serum as normal mice. Second, knockout mice have many skeletal abnormalities such as dangerously fragile and porous bones, hunched backs, and splayed limbs. These abnormalities are caused by a lack of collagen, a major structural component of bone. Third, the ability of knockout mice to use sugar (glucose) is abnormal. At birth, the mice are apparently healthy in this regard, with normal levels of glucose and glucose products in their livers and normal numbers of insulin-producing beta cells in their pancreases. After three weeks, juvenile knockout mice develop severe diabetes. Their glucose levels soar to three to four times normal levels and the number of beta cells in their pancreases is reduced. After six weeks, insulin-producing beta cells are rare or completely absent.

In one experiment, Cavener and colleagues focused on the mechanisms behind the retarded growth of PERK knockout mice. By injecting the PERK knockout mice with IGF-1 twice daily during the first three weeks of life, researchers were able to accelerate the neonatal growth rate of the mice. Their growth was markedly improved but not restored to normal rates. They concluded that defects in the regulation of IGF-1 were at least partially responsible for the retarded growth rates in PERK deficient mice. The improvement produced by treating the mice with IGF-1 has exciting implications for developing therapeutic interventions for people diagnosed with Wolcott-Rallison Syndrome.

Cavener emphasizes that it is extremely important that the growth and skeletal problems occur earlier than and independently from the diabetes in these mice. "Knowing which problems are the primary effects of diabetes, and which are independent effects produced by a defect in the same gene, may be of great importance in treating the disease," Cavener predicts.

In a second experiment, Cavener and his colleagues demonstrated the complexity of the various functions of the PERK gene. They produced transgenic mice that carried a single copy of the PERK gene that was expressed only in the insulin-producing beta cells. Normal mice carry two copies of this gene and knockout mice have none. The PERK gene produced a dramatic change in glucose metabolism. Unlike PERK deficient mice, transgenic mice do not become diabetic as juveniles and retain normal numbers of insulin-producing beta cells.

During the neonatal period the transgenic mice still suffered from retarded growth. Surprisingly, Cavener’s team found that the transgenic mice resumed normal rates of growth as they aged past three weeks. This finding suggests that the slowed rate of growth in juvenile knockout mice is probably a secondary effect of diabetes.

The results of this research program lead Cavener to theorize that the major function of PERK is to sense the activity of cells that secrete such vital proteins as insulin and collagen and to signal the cells to adjust their rate of secretion or cell division to match the needs of the body for these important proteins. Much of the current research in Cavener’s group focuses on testing this hypothesis.

In addition to Cavener, other members of the research team include: Ami Frank, Kaori Iida, Sheng’ai Li, Yulin Li, Shun-Hsin Liang, Barbara McGrath, Jeff O’Neil, Jamie Reinert, Frank Zambito, Peichuan Zhang, and Wei Zhang, all of Penn State; Maureen Gannon of the Vanderbilt University School of Medicine; Kun Ma of the Indiana University School of Medicine, and Kelly McNaughton of Vanderbilt University. This research was funded by the Culpeper Foundation, the Vanderbilt Clinical Nurition Research Unit, Penn State University, and National Institutes of Health grant GM56957 to Cavener.


###
CONTACTS: Douglas R. Cavener: phone 814-865-4562, e-mail drc9@psu.edu
Barbara K. Kennedy (PIO): 814-863-4682, science@psu.edu

Barbara K. Kennedy | EurekAlert!
Further information:
http://www.psu.edu/
http://www.science.psu.edu/alert/Cavener4-2003.htm

More articles from Health and Medicine:

nachricht Vanishing capillaries
23.03.2017 | Technische Universität München

nachricht How prenatal maternal infections may affect genetic factors in Autism spectrum disorder
22.03.2017 | University of California - San Diego

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

Researchers use light to remotely control curvature of plastics

23.03.2017 | Power and Electrical Engineering

Sea ice extent sinks to record lows at both poles

23.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>