International research collaboration narrows focus on genetic cause of Kawasaki disease
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UC-San Diego investigators say findings may impact treatment of additional diseases.
Researchers from Japan’s RIKEN SNP Research Center, collaborating with a team at the University of California, San Diego (UCSD), have discovered a new genetic variation that affects a child’s risk of getting Kawasaki disease (KD), an illness characterized by acute inflammation of the arteries throughout the body. The genetic variation influences immune activation and the response to standard treatment, as well as the risk of developing coronary artery aneurysms – a swelling of the artery that can result in blood clots and heart attack – as a complication of KD.
Lead author, Yoshi Onouchi, M.D., Ph.D., SNP Research Center, RIKEN, Yokohama, Japan, used DNA from hundreds of U.S. children and their parents, collected through the Kawasaki Disease Research Center at Rady Children’s Hospital San Diego (RCHSD), Department of Pediatrics, UCSD School of Medicine.
“This was a wonderful collaboration,” said co-author, Jane Burns, M.D., professor and chief, Division of Allergy, Immunology, and Rheumatology, UCSD Department of Pediatrics. “Dr. Onouchi used our DNA to make this observation. Now we are building on that observation.”
Kawasaki Disease, a pediatric illness characterized by fever and rash, is not a rare illness but it is most prevalent in Japan. In San Diego County, 20 to 30 children per 100,000 children less than five years of age are affected each year. More than 50 new patients are treated annually at RCHSD. The illness is four to five times more common than some more publicly recognized diseases of children such as tuberculosis or bacterial meningitis.
If untreated, KD can lead to lethal coronary artery aneurysms. KD tends to run in families, suggesting that there are genetic components to disease risk. It is also 10 to 20 times more common in Japanese and Japanese American children than in children of European descent.
Researchers identified a region on chromosome 19 linked with the disease. In particular, a series of variants across four genes in the region appeared more frequently in individuals with the disease than those in the healthy control group.
The team focused on one of these genes, ITPKC, which appeared to be the most likely candidate. The gene lies in a signaling pathway that affects the activation of T cells, one arm of the body’s immune response system. ITPKC encodes an enzyme that is part of a signaling pathway with a critical role in T cell activation. The authors showed that one of the risk variants reduces the expression of ITPKC, and that lower levels of ITPKC lead to over-activation of T cells.
“This single gene jumped out as an obvious candidate because it is involved in immune activation, and KD is a disease of immune over-activation,” said Burns. “This was great detective work to decipher the function of this variant.”
Study authors suggest that the association of ITPKC with Kawasaki disease may have immediate clinical implications. Up to 20% of children who have KD are resistant to the standard treatment with intravenous immunoglobulin. This therapy is more likely to fail in individuals with the ITPKC risk variant. If these individuals could be identified with a genetic test, they could be offered alternative, more intensive therapies.
Further studies will identify additional sites of genetic variation and may capture enough of the genetic influence that a diagnostic test can be devised to identify children at increased risk. These children with KD would be candidates for more aggressive therapy.
“A significant number of KD patients suffer irreversible coronary artery damage, which can lead to heart attack, heart failure, or require transplant,” noted Burns. “Our goal at RCHSD is to create a genetic test for KD patients that will indicate whether the patient is at increased risk. If that’s the case, we can use additional treatments and potentially reduce future complications.”
In addition, the finding may have implications for understanding the genetic thermostat that regulates the intensity of a person’s immune response to inflammation. Investigators are now looking at what impact this genetic variation might have on initiating other inflammatory conditions, such as atherosclerosis and myocarditis, an inflammation of the heart muscle often caused by a viral infection.
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The Kawasaki Disease Research Program is a joint collaboration between the Departments of Pediatrics and Sociology at University of California, San Diego (UCSD), the Climate Center at Scripps Institution of Oceanography, and Rady Children’s Hospital San Diego. The Program was created to help foster excellence in care for patients with Kawasaki Disease (KD) and to support clinical, laboratory, and epidemiologic investigation into the etiology, pathophysiology, and natural history of the disease. The program brings together investigators from more than 15 countries with diverse research interests and expertise to work together to further our understanding of this enigmatic disease.
Kawasaki Disease is often accompanied by the following symptoms: high fever and irritability; rash; swelling and redness of the hands and feet; bloodshot eyes; red mouth, lips, and throat; and swollen lymph nodes in the neck. It affects children almost exclusively; most patients are under 5 years of age. For reasons still unknown, males acquire the illness almost twice as often as females.
Obesity reduces a woman’s chances of conception
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Those with their BMI at 35 were 26 percent less likely to become pregnant whereas those with MI at 40 had their odds of getting pregnant reduced by 43 percent.
Obesity worsens a woman’s prospect of conception and reduces her chances of getting pregnant significantly, according to a study published by Dutch researchers in the journal Human Reproduction.
The study of more than 3,000 couples who were followed up between 2002 and 2004 in 24 hospitals in the Netherlands found women who had a body mass index above 30 (defined as obese) were significantly less likely to get pregnant.
But the study has a number of limitations including the fact that the researchers did not track the timing and frequency of sexual intercourse, which is relevant because they affect the likelihood. For example, early research reported that obese women have sex less frequently than women with normal weight.
Protein Fingerprinting Made Easy
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Combining some traditional experimental methods of molecular biology with computational methods of artificial intelligence, a group of researchers from Ruder Boškovic Instititute and Faculty of Natural Sciences and Mathematics from Zagreb, Croatia, demonstrated a novel approach for producing ‘protein fingerprints’ of diverse tissues. This result could lead to the development of new convenient methods in medical diagnostics.
Being directly responsible for a great majority of processes in living cells, proteins are the most important class of biological molecules. They are literally ‘molecular machines’ which facilitate the import of nutrients into the cell and expulsion of waste products from it, production of energy and transportation of material within the cell, as well as cellular respiration and mechanical motion. Due to their immense importance, proteins are among the most vigorously studied topics in biology today.
Over half a million different protein species have been identified in humans, each of them related to particular types of human cells. Different tissues, such as muscles, bones, nerves or skin, are distinguished by the unique ‘protein fingerprint’ – the specific relative abundance of different proteins contained in their cells. Moreover, pathological changes in any type of tissue necessarily have an impact on the tissue’s protein composition, and therefore protein fingerprinting can be used for early diagnostics and identification of various diseases such as tumors or infections.
Unfortunately, producing a good quality protein fingerprint has until now been a complicated, time consuming and expensive enterprise. However, based on their research of tumors conducted on horseradish plant tissue, the Croatian team proposed a novel approach to bypass this obstacle.
Applying computational methods of artificial intelligence, they ‘trained’ a computer to precisely extract the most relevant information on the protein fingerprint from rather ‘fuzzy’ experimental data obtained by 1D protein electrophoresis, a well known, simple, quick and cheap experimental method of molecular biology. Their result hence opens up the possibility for development of a cheap, convenient and reliable method for producing good quality protein fingerprints.
The study ‘Enhanced analytical power of SDS-PAGE using machine learning algorithms’ will be published in the January issue of “Proteomics” (DOI 10.1002/pmic.200700555)
Adapted from materials provided by Rudjer Boskovic Institute.
UQ Health And Medical Researchers Recognized In Awards
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Three researchers from The University of Queensland have been recognised in the inaugural National Health and Medical Research Council (NHMRC) Awards.
Professors John Hancock and Robert Parton, both from UQ’s Institute for Molecular Bioscience (IMB) and Dr David Copland from the School of Health & Rehabilitation Sciences were among a select group of winners honoured at a ceremony held in Canberra.
The NHMRC Awards recognise a number of outstanding Australians for their contributions to health and medical research. The awards are designed to show the NHMRC’s appreciation to the research and ethics community for their considerable scientific research, innovation and leadership. Professor David Siddle, UQ’s Deputy Vice-Chancellor (Research), said the awards were testament to the outstanding work of the three researchers in areas that will one day improve the health of many people.
“These awards recognise the ground-breaking work of three outstanding researchers,” Professor Siddle said.
“In addition to the fundamental research, these talented researchers are working on solutions to problems such as cancer, muscular dystrophy and treatments for brain injury and disease.”
Professors Hancock and Parton received the NHMRC Achievement Award - Program Grant, which recognises their work in studying the surface of the cell.
Far from being a smooth, uniform area, the cell surface is actually organised into different domains with distinct functions. The researchers will map these domains and identify their functions, which should allow the development of therapeutic strategies aimed at combating the changes associated with cell transformation in cancer and other human diseases such as muscular dystrophy.
Professor Hancock is the Deputy Director (Research) of the IMB and a world authority on Ras proteins, which are located on the underside of the cell membrane and play a role in triggering 30 percent of all human tumours.
Professor Parton is an expert on caveolae, small pits in the cell surface, which have been linked to muscular dystrophy, liver regeneration and obesity. The two recently received a $5 million Program Grant to support their study.
Dr Copland received the NHMRC Achievement Award - Career Development Award - Clinical Level 2 (Senior researcher 7-12 years post Doctorate), which recognises his work to understand the effects of neurological injury or disease on language and to shed light on the brain mechanisms underpinning language treatment and recovery.
He is internationally recognised for research that has significantly increased our understanding of the effects of stroke and neurodegenerative diseases on language and communication. He is also involved in training a large cohort of PhD students as future researchers in this area.
His current work seeks to map the brain mechanisms associated with language treatments and to identify how to optimise language function after neurological damage.
Molecular Code Broken For Drug Industry’s Pet Proteins
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All cells are surrounded by protective, fatty membranes.In the cell membrane there are thousands of membrane proteins that transport nutritional substances, ions, and water through the membrane. Membrane proteins are also necessary for cells to recognize each other in the body and for a nervous system, for example, to be formed. Researchers at Stockholm University in Sweden have now managed to reveal the “molecular code” that governs the insertion of proteins in the cell membrane.
About 25 percent of all proteins in a cell are found in the cell membrane. Since they regulate all communication between the inside of the cell and the surrounding environment, many membrane proteins are crucial to the life of the cell. Disruptions of their functions often lead to diseases of various kinds. For the drug industry, membrane proteins are high priority “drug targets.” This work is reported in an article being published on December 13 in the journal Nature.
To be suitable for deployment in the fatty cell membrane, all membrane proteins must be lipophiles (”fat-lovers”). All cells have special machinery for producing and dealing with “fatty” proteins and to see to it that they are deployed in proper manner in the cell membrane. The Stockholm University scientists have developed a method for the detailed study of the properties of a membrane protein that are required for it to be recognized by the cell machinery. A couple of years ago the research team published a first article in Nature in which they managed to show that there is a “fat threshold” that determines whether a protein can be deployed to a membrane or not. In this new study they have fully revealed the molecular code that governs the structure of membrane proteins.
“Now that we have deciphered the code, we can determine with a high degree of certainty which parts of a protein will fasten in the membrane.” says Gunnar von Heijne.
This new knowledge will help researchers all over the world who are trying to understand more about the cell and its membrane, not least in the drug industry.
“Interest in membrane proteins is at a peak right now, and our findings can be key pieces of the puzzle for pharmaceutical chemists working with drug design, for example,” says Gunnar von Hejne.
Name of article: Molecular code for transmembrane-helix recognition by the Sec61 translocon. Nature, December 13.Adapted from materials provided by Stockholm University.