Drugs that target FleN could lead to anti-biofilm therapies

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Cystic Fibrosis
Article Date: 19 Aug 2013 - 0:00 PDT Current ratings for:
Drugs that target FleN could lead to anti-biofilm therapies

The evolution of hyperswarming, pathogenic bacteria might sound like the plot of a horror film, but such bugs really have repeatedly evolved in a lab, and the good news is that they should be less of a problem to us than their less mobile kin. That's because those hyperswarmers, adorned with multiple whipping flagella, are also much worse at sticking together on surfaces in hard-to-treat biofilms. They might even help us figure out a way to develop anti-biofilm therapies for use in people with cystic fibrosis or other conditions, say researchers who report their findings in Cell Reports, a Cell Press publication.

The findings are also a textbook example of real-time experimental evolution. What's more, says Joao Xavier of Memorial Sloan Kettering Cancer Center, they are a "unique example of strikingly parallel molecular evolution."

In other words, the evolution that he and his team witnessed was repeatable, all the way down to the molecular level.

The researchers didn't set out with the goal to evolve hyperswarmers, but they did passage Pseudomonas aeruginosa on special plates over a period of days. On those plates, bacteria that could spread out had an advantage in harvesting nutrients from the surface, and within a matter of days, some of those bacteria started hyperswarming.

Investigation of the bacteria showed that P. aeruginosa gained its hyperswarming ability through a single point mutation in a flagellar synthesis regulator (FleN). As a result, the bacteria, which usually have one single flagellum, were locked into a multi-flagellated state. They became better at moving around to cover a surface, but much worse at forming densely packed, surface-attached biofilm communities. All told, the researchers saw this new ability independently arise 20 times.

"The fact that the molecular adaptations were the same in independent lineages suggests evolution may be, to some extent, predictable," says Xavier.

The findings may be very important because biofilms are a major problem in clinical settings. Infectious biofilms are hard to remove and difficult to kill with antibiotics. Drugs that target FleN or that otherwise make bacteria better at spreading out and worse at settling down could leave them more vulnerable to antibiotics and easier to get rid of.

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New target inhibiting the progression of Alzheimer's disease

Main Category: Alzheimer's / Dementia
Article Date: 19 Aug 2013 - 0:00 PDT Current ratings for:
New target inhibiting the progression of Alzheimer's disease

To stop the progression of Alzheimer's disease in the early stage, it is necessary to identify new therapeutic targets.

Prof. Yunpeng Cao and team from the First Affiliated Hospital of China Medical University examined striatal-enriched phosphatase 61 expression in the brain tissues of Alzheimer's disease rats using in vivo and in vitro models, and analyzed the molecular mechanism by which striatal-enriched phosphatase 61 regulates N-methyl-D- aspartate receptor 2B transport.

The researchers found that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid- beta 1-induced increased activity of striatal-enriched phosphatase 61. In addition, the phos-phorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B.

Collectively, these findings, published in Neural Regeneration Research (Vol. 8, No. 21, 2013), indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer's disease. Thus, striatal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer's disease.

Article: " What is the new target inhibiting the progression of Alzheimer's disease?," by Lin Zhang1, Jing Yang2, Yunpeng Cao1 (1 Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China; 2 Provincial Key Laboratory of Cardiovascular and Cerebrovascular Drug Basic Research, Liaoning Medical University, Jinzhou 121001, Liaoning Province, China). Neural Regen Res. 2013;8(21):1938-1947. doi:10.3969/j.issn.1673-5374.2013.21.002

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Researchers discover molecular target for the bacterial infection brucellosis

Main Category: Infectious Diseases / Bacteria / Viruses
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Researchers discover molecular target for the bacterial infection brucellosis

UC Davis scientists have uncovered a potential drug target for the development of an effective therapy against the debilitating, chronic form of the bacterial disease brucellosis, which primarily afflicts people in Mediterranean and Middle Eastern countries.

Brucellosis, which affects about 500,000 people worldwide each year, typically is caused by ingestion of unsterilized milk or close contact with body secretions from infected animals. Symptoms include intermittent or irregular fever of variable duration, headache, weakness, profuse sweating, chills, weight loss and generalized aching. It can also cause long-lasting or chronic symptoms such as recurrent fevers, joint pain and fatigue.

In a paper published online in the journal Cell Host & Microbe, the researchers reported that they have identified the cells that harbor the B. abortus bacteria during the persistent phase of the brucellosis. The cells, known as alternatively activated macrophages (AAMs), are a recently identified category of immune defense cells.

The researchers also determined that the biological pathway peroxisome proliferator activated receptor ?, abbreviated as PPAR?, is responsible for altering the metabolism of AAMs so that they supply B. abortus with the energy in the form of glucose that enables bacteria to survive and replicate and thereby sustain the chronic phase of the infectious disease. Other labs also have shown that PPAR? control a cell's metabolism.

"We found that PPAR? induces a metabolic shift in these cells that causes them to generate glucose," said Renee Tsolis, associate professor of medical microbiology and immunology at UC Davis who led the study.

"Starving the B. abortus bacteria by inhibiting the PPAR? pathway may be a new approach to eradicating the chronic, difficult-to-treat form of Brucellosis infection that usually occurs because antibiotic therapy was not used during the acute, or early, phase of the infection," said Tsolis.

Tsolis and her collaborators were the first to discover PPAR?'s role in brucellosis and to determine that AAMs harbor the bacteria during the chronic stage of the disease. The identification of the bacteria's niche is another important clue for the development of a more effective treatment, she said.

In a series of experiments, Tsolis and collaborators found that the gene encoding PPAR? is very active during chronic Brucellosis infection, but not during acute infection, and that the B. abortus bacteria did not survive in AAMs when deprived of glucose.

When the researchers inactivated the protein that normally transports glucose, the bacteria stopped reproducing, and the infection no longer was chronic, she said.

In mice infected with B. abortus, Tsolis and collaborators treated the animals with GW9662, a PPAR inhibitor. The researchers administered the inhibitor before the infection became chronic, or long lasting. The inhibitor significantly reduced the amount of AAMs and B. abortus bacteria in the mice.

"These results suggested that inhibition of PPARreduced the bacteria's survival by reducing the abundance of AAMs during chronic infection," said Tsolis.

Conversely, when the researchers treated the B. abortus-infected mice with Rosiglitazone, a drug that boosts PPAR activity, the bacteria increased by two-fold during the acute phase and four-fold during the chronic phase of infection. Rosiglitazone and other drugs that boost PPARare used to treat type 2 diabetes because they lower blood glucose by increasing cellular glucose uptake.

In other experiments, the researchers showed that AAMs, one of two categories of macrophages, are abundant in the spleen during chronic brucellosis but not during the acute, or initial, phase of the infection, which is dominated by classically activated macrophages (CAM), the second category of these immune cells.

In addition to profuse sweating, symptoms of brucellosis infection include joint and muscle pain. Among the complications of chronic infection are arthritis and endocarditis, a serious inflammation of one of the four heart valves. Brucellosis rarely occurs in the U.S., with about 100 to 200 cases reported each year, according to the U.S. Centers for Disease Control and Prevention.

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The title of the journal paper is “PPAR?-Mediated Increase in Glucose Availability Sustains Chronic Brucella abortus Infection in Alternatively Activated Macrophages.”

Authors also include: Mariana N. Xavier, Maria G. Winter, Alanna M. Spees, Andreas B. den Hartigh, Kim Nguyen, Christelle M. Roux, Vidya L. Atluri, Tobias Kerrinnes, A. Marijke Keestra and Andreas J. Baumler of UC Davis; Denise M. Monack of Stanford University, Palo Alto, CA; and Paul A. Luciw, Richard A. Eigenheer, Renato L. Santos and Teane M.A. Silva of the Universidade Federal de Minas Gerais in Brazil. Cell Host & Microbe, Volume 14, Issue 2, 159-170, 14 August 2013; 10.1016/j.chom.2013.07.009

University of California - Davis Health System

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CDK6 represents a promising target for anti-cancer therapy

Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 15 Aug 2013 - 0:00 PDT Current ratings for:
CDK6 represents a promising target for anti-cancer therapy

Cell division is tightly controlled by a number of genes and because of the importance of ensuring that the process stays in check - mistakes frequently lead to cancer - mammalian cells often have several inbuilt layers of security. The two cyclin-dependent kinases CDK4 and CDK6 are widely believed to have almost identical functions, so either one of them can compensate for problems with the other. New work at the University of Veterinary Medicine, Vienna challenges this view and shows that, unlike CDK4, CDK6 also promotes the growth of blood vessels. This explains why CDK6 is so frequently misregulated in certain types of cancer. The results are published in the current issue of the prestigious international journal Cancer Cell.

Cancer in humans is frequently associated with unusually high amounts of one or more proteins responsible for controlling the rate at which cells divide. As an example, excessive amounts of the cyclin-dependent kinase CDK6 are often found in types of cancer such as lymphoma. Together with a number of collaborators within Vienna and beyond, Karoline Kollmann of the University of Veterinary Medicine, Vienna (Vetmeduni) has now shown that CDK6 is part of a multiprotein complex that stimulates the production of one of the so-called INK4 family members (confusingly termed p16INK4a), which suppresses tumour growth. In other words, the cell has an inbuilt mechanism to help it cope with excessive amounts of CDK6.

The problems really start when p16INK4a is missing, as is frequently the case in lymphomas or leukaemias. Now the high levels of CDK6 are unchecked and so can lead directly to a stimulation of cell division. Furthermore, Kollmann and her colleagues showed that another CDK6-containing complex can also promote the production of an additional factor, known as VEGF-A, that increases the growth of blood vessels and thus ensures that the cells in the growing tumours are supplied with sufficient energy and oxygen to multiply. CDK6 is the first factor to be shown to be involved in regulating tumour growth while simultaneously helping to supply tumours with blood.

As its name implies, CDK6 is a kinase, i.e. it adds phosphate groups to other proteins and thereby alters their activity. In a further twist to the tale, the Vetmeduni scientists have shown that CDK6 can still exert its effects on p16INK4a and VEGF-A when it lacks its kinase activity: a mutant form of the CDK6 protein with the kinase function inactivated retains the ability to regulate expression of the p16INK4a and VEGF-A genes.

Veronika Sexl, Head of the Vetmeduni's Institute of Pharmacology and Toxicology, where the work was performed, notes the medical importance of her group's findings. "Because it is known to be involved in so many cancers, CDK6 represents a promising target for anti-cancer therapy and lots of labs are trying to design specific inhibitors. But their efforts are focused on inhibiting CDK6's kinase function. We have shown that CDK6 has an additional, kinase-independent mode of action that is responsible for the uncontrolled cell growth and increased production of blood vessels that are a hallmark of cancer. CDK6 inhibitors will also need to block this new function if they are to be effective in treating cancer."

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The paper - A new kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis by Karoline Kollmann, Gerwin Heller, Christine Schneckenleithner, Wolfgang Warsch, Ruth Scheicher, Rene G. Ott, Markus Schäfer, Sabine Fajmann, Michaela Schlederer, Ana-Iris Schiefer, Ursula Reichart, Matthias Mayerhofer, Christoph Hoeller, Sabine Zoechbauer-Mueller, Dontscho Kerjaschki, Christoph Bock, Lukas Kenner, Gerald Hoefler, Michael Freissmuth, Anthony R. Green, Richard Moriggl, Meinrad Busslinger, Marcos Malumbres and Veronika Sexl; Cancer Cell, Volume 24, Issue 2, 167-181, 12 August 2013; 10.1016/j.ccr.2013.07.012

University of Veterinary Medicine -- Vienna

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Potential new anti-cancer target: 'dark-horse' molecule

Main Category: Colorectal Cancer
Also Included In: Cancer / Oncology;  GastroIntestinal / Gastroenterology
Article Date: 14 Aug 2013 - 0:00 PDT Current ratings for:
Potential new anti-cancer target: 'dark-horse' molecule

Australian researchers have identified a molecule called interleukin-11 as a potential new target for anti-cancer therapies.

Until now, the importance of interleukin-11 in cancer development has been underestimated, but researchers have recently identified this molecule as a 'dark horse' for the development of cancer. Their discovery suggests blocking interleukin-11 signalling could ultimately provide an exciting new approach to the treatment of bowel and stomach cancer, which are two of the most common cancers worldwide.

When a tumour develops, the normal (non-cancerous) tissues around it can become inflamed, and produce many different molecules, including the two related proteins interleukin-11 and interleukin-6. These hormone-like signalling molecules, referred to as cytokines, are thought to promote the growth and spread of cancer cells, but interleukin-11 was thought to have only a minor, if any, role during cancer development.

However Dr Tracy Putoczki and Associate Professor Matthias Ernst from the Walter and Eliza Hall Institute's Cell Signalling and Cell Death division have now shown that interleukin-11 is one of the most important cytokines that stimulate the growth and spread of cancers. Working with scientists at the Melbourne-based pharmaceutical company CSL Ltd, they discovered that blocking interleukin-11 in models of stomach and bowel cancer stopped tumour growth and could lead to tumour shrinkage, making this cytokine a promising potential new target for treating many types of solid cancers.

Dr Putoczki and Associate Professor Ernst made most of their discoveries while working at the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research, where Associate Professor Ernst is an institute member. Their findings are published online in the journal Cancer Cell.

Dr Putoczki said the team was stunned to discover that interleukin-11 was much more potent in promoting cancer development than interleukin-6. "When considering which cytokines drive cancer development, interleukin-6 has always been in the spotlight," she said. "Despite being very similar to interleukin-6, interleukin-11 has often been overlooked by cancer researchers. Our new research now shows that it might in fact be very important."

Associate Professor Ernst said the team had begun to explore how the discovery could be applied to potential new anti-cancer therapies. "Treating cancers with agents that block cytokine signalling is an exciting new approach that potentially has advantages over current treatment strategies," he said. "Drugs that block the action of cytokines have previously been developed for both inflammatory disease and cancer and, in the case of interleukin-11, our work does not suggest the likelihood of undesirable side-effects. Moreover, agents that inhibit interleukin-6 signalling are already in clinical trials for ovarian, kidney, prostate and breast cancer. Our discovery paves the way for trials of agents that stifle interleukin-11."

Dr Andrew Nash, senior vice president for research at CSL, agreed that the research had identified a potentially important role for interleukin-11 in stomach and bowel cancer. "We have developed a number of potential drug candidates that target the interleukin-11 receptor and this data provides preclinical evidence supporting progression into clinical studies," Dr Nash said.

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The research was supported by the Ludwig Insitute of Cancer Research, CSL Ltd, the Australian National Health and Medical Research Council, Cancer Australia, Cure Cancer Australia, German Cancer Aid, and the Victorian Government.

Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically Cancer Cell, Volume 24, Issue 2, 257-271, 12 August 2013. 10.1016/j.ccr.2013.06.017

Walter and Eliza Hall Institute

Ludwig Institute for Cancer Research

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Researchers target 'cell sleep' to lower chances of cancer recurrence and make cancer drugs more effective

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The study is a collaboration with the Dana-Farber Cancer Institute in Boston and the Catholic University in Leuven, Belgium.

Additional co-authors of this study include Sergei Boichuk, M.D., Ph.D., Joshua A. Parry, B.S., Kathleen R. Makielski, M.S., Julianne L. Baron, B.S., James P. Zewe, B.S., Keith R. Mehalek, M.S., and Danushka S. Seneviratne, B.S., all of UPCI’s Cancer Virology Program; James A. DeCaprio, M.D., and Larisa Litovchick, Ph.D., both of the Dana-Farber Cancer Institute; Patrick Schöffski, M.D., M.P.H., Maria Debiec-Rychter, M.D., Ph.D., and Agnieszka Wozniak, Ph.D., all of the Catholic University of Leuven in Belgium; and Nina Korzeniewski, Ph.D., of the University of Heidelberg School of Medicine in Germany.

This research was supported by Research Scholar Grant RSG-08-092-01-CCG from the American Cancer Society, the GIST Cancer Research Fund, The Life Raft Group and a number of private donations.

University of Pittsburgh Schools of the Health Sciences

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Study reveals target for drug development for temporomandibular joint disorder (TMJD) - a chronic jaw pain disorder

Main Category: Dentistry
Also Included In: Pain / Anesthetics
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Study reveals target for drug development for temporomandibular joint disorder (TMJD) - a chronic jaw pain disorder

Temporomandibular joint disorder (TMJD) is the most common form of oral or facial pain, affecting over 10 million Americans. The chronic disorder can cause severe pain often associated with chewing or biting down, and lacks effective treatments.

In a study in mice, researchers at Duke Medicine identified a protein that is critical to TMJD pain, and could be a promising target for developing treatments for the disorder. Their findings are published in the August issue of the journal PAIN.

Aside from cases related to trauma, little is known about the root cause of TMJD. The researchers focused on TRPV4, an ion channel protein that allows calcium to rapidly enter cells, and its role in inflammation and pain associated with TMJD.

"TRPV4 is widely expressed in sensory neurons found in the trigeminal ganglion, which is responsible for all sensations of the head, face and their associated structures, such as teeth, the tongue and temporomandibular joint," said senior study author Wolfgang Liedtke, M.D., PhD, associate professor of neurology and neurobiology at Duke. "This pattern and the fact that TRPV4 has been found to be involved in response to mechanical stimulation made it a logical target to explore."

The researchers studied both normal mice and mice genetically engineered without the Trpv4 gene (which produces TRPV4 channel protein). They created inflammation in the temporomandibular joints of the mice, and then measured bite force exerted by the mice to assess jaw inflammation and pain, similar to how TMJD pain is gauged in human patients. Given that biting can be painful for those with TMJD, bite force lessens the more it hurts.

The mice without the Trpv4 gene had a smaller reduction in bite force - biting with almost full force - suggesting that they had less pain. In normal mice there was more TRPV4 expressed in trigeminal sensory neurons when inflammation was induced. The increase in TRPV4 corresponded with a greater reduction in bite force.

The researchers also administered a compound to normal mice that blocked TRPV4, and found that inhibiting TRPV4 also led to smaller reductions in bite force, similar to the effects of the mice engineered without the Trpv4 gene.

Surprisingly, the researchers found comparable bone erosion and inflammation in the jaw tissue across all mice, regardless whether the mice had TRPV4 or not.

"Remarkably, the damage is the same but not the pain," Liedtke said. "The mice that had the most TRPV4 appeared to have the most pain, but they all had similar evidence of temporomandibular joint inflammation and bone erosion in the jawbone as a consequence of the inflammation."

The results suggest that TRPV4 and its expression in trigeminal sensory neurons contribute to TMJD pain in mice. Given the lack of effective treatments for this chronic pain disorder, TRPV4 may be an attractive target for developing new therapies.

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In addition to Liedtke, Duke study authors include senior pain researcher Yong Chen, Ji Hee Hong, Suk Hee Lee, Puja K. Parekh and Carlene Moore of the Department of Neurology; Amy L. McNulty, Nicole E. Rothfusz and Farshid Guilak of the Department of Orthopaedic Surgery; Fan Wang of the Department of Cell Biology/Neurobiology; and Andrea B. Taylor of the Departments of Community and Family Medicine and Evolutionary Anthropology. Susan H. Williams of the Heritage College of Osteopathic Medicine at Ohio University and Robert W. Gereau IV of the Department of Anesthesiology at Washington University in St. Louis also contributed to this research.

The research was supported by the National Institutes of Health (DE018549, DE19440, DE19440S1, NS48602, AR048182 and DE018549-S); Duke Institute for Brain Sciences; Nicholas School of the Environment, Duke University; and Keimyung University School of Medicine in South Korea.

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Identification of key target responsible for triggering detrimental effects in brain trauma

Main Category: Neurology / Neuroscience
Also Included In: Stroke
Article Date: 29 Jul 2013 - 1:00 PDT Current ratings for:
Identification of key target responsible for triggering detrimental effects in brain trauma

Researchers studying a type of cell found in the trillions in our brain have made an important discovery as to how it responds to brain injury and disease such as stroke. A University of Bristol team has identified proteins which trigger the processes that underlie how astrocyte cells respond to neurological trauma.

The star-shaped astrocytes, which outnumber neurons in humans, are a type of glial cell that comprise one of two main categories of cell found in the brain along with neurons. The cells, which have branched extensions that reach synapses (the connections between neurons) blood vessels, and neighbouring astrocytes, play a pivotal role in almost all aspects of brain function by supplying physical and nutritional support for neurons. They also contribute to the communication between neurons and the response to injury.

However, the cells are also known to trigger both beneficial and detrimental effects in response to neurological trauma. When the brain is subjected to injury or disease, the cells react in a number of ways, including a change in shape. In severe cases, the altered cells form a scar, which is thought to have beneficial, as well as detrimental effects by allowing prompt repair of the blood-brain barrier, and limiting cell death, but also impairing the regeneration of nerve fibres and the effective incorporation of neuronal grafts - where additional neuronal cells are added to the injured site.

The cells change shape via the regulation of a structural component of the cell called the actin cytoskeleton, which is made up of filaments that shrink and grow to physically manoeuvre parts of the cell. In the lab, the team cultured astrocytes in a dish and were able to make them change shape by chemically or genetically manipulating proteins that control actin, and also by mimicking the environment that the cells would be exposed to during a stroke.

By doing so the team found that very dramatic changes in cell shape were caused by controlling the actin cytoskeleton in the in vitro stroke model. The team also identified additional protein molecules that control this process, suggesting that a complex mechanism is involved.

Dr Jonathan Hanley from the University's School of Biochemistry said: "Our findings are crucial to our understanding of how the brain responds to many disorders that affect millions of people every year. Until now, the details of the actin-based mechanisms that control astrocyte morphology were unknown, so we anticipate that our work will lead to future discoveries about this important process."

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The research was funded by the Wellcome Trust with additional support from the EU and Medical Research Council [MRC].

Paper: The antagonistic modulation of Arp2/3 activity by N-WASP/WAVE2 and PICK1 defines dynamic changes in astrocyte morphology by Kai Murk (1), Elena M. Blanco Suarez (1), Louisa M.R. Cockbill (1), Paul Banks (2) and Jonathan G. Hanley (1) is published in advance online in the journal Cell Science. URL:

1. School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, UK

2. School of Physiology and Pharmacology, Medical Sciences Building, University of Bristol, Bristol, UK

University of Bristol

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Study finds druggable target for pulmonary hypertension

Main Category: Respiratory / Asthma
Also Included In: Hypertension;  Genetics
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Study finds druggable target for pulmonary hypertension

Columbia University Medical Center (CUMC) scientists have identified new genetic mutations that can cause pulmonary arterial hypertension (PAH), a rare fatal disease characterized by high blood pressure in the lungs. The mutations, found in the gene KCNK3, appear to affect potassium channels in the pulmonary artery, a mechanism not previously linked to the condition. Cell culture studies showed that the mutations' effects could be reversed with a drug compound known as a phospholipase inhibitor. The study was published in the online edition of the New England Journal of Medicine.

"The most exciting thing about our study is not that we've identified a new gene involved in pulmonary hypertension, but that we've found a drug that can 'rescue' some mutations," said co-senior author Wendy K. Chung, MD, PhD, associate professor of pediatrics and medicine at CUMC. "In genetics, it's common to identify a gene that is the source of a disease. However, it's relatively rare to find potential treatments for genetic diseases."

PAH is a progressive disorder characterized by abnormally high blood pressure in the pulmonary artery, which reduces blood flow from the right side of the heart to the lungs. The heart can compensate by pumping harder, but over time this can weaken the heart muscle and lead to right-sided heart failure. Common symptoms of PAH include shortness of breath, dizziness, and fainting. About 1,000 new cases are diagnosed in the United States each year. The disorder is twice as common in females as in males. There is no cure for PAH and few effective treatments. Most patients with PAH die within 5-7 years of diagnosis.

Some cases of PAH are caused by inherited genetic defects. Most of these "familial" cases have been linked to mutations in a gene called BMPR2 (bone morphogenetic protein receptor, type II), which was identified simultaneously in 2000 by two independent research teams, one led by the late Robin Barst and Jane Morse, CUMC researchers. However, the majority of cases are idiopathic in origin (of unknown cause). Other forms of PAH can be triggered by autoimmune diseases, congenital heart defects, infections (such as schistosomiasis), and medications (such as the now-banned diet-drug combination commonly known as fen-Phen).

Dr. Chung and her colleagues discovered the new mutations by sequencing the exomes (the portion of the genome that codes information to make proteins) of families with PAH without identified mutations. KCNK3 mutations were found in 3.2 percent of those with familial disease and in 1.3 percent of those with idiopathic PAH.

The team found that the mutations alter the function of potassium channels by reducing the activity of these channels. Potassium channels help maintain the vascular tone of the pulmonary artery and help it respond to low levels of oxygen.

"We were surprised to learn that KCNK3 appears to play a role in the function of potassium channels in the pulmonary artery," said Dr. Chung. "No one had suspected that this mechanism might be associated with PAH." The other gene linked to the disorder, BMPR2, is thought to cause PAH by ultimately promoting growth and multiplication of smooth muscle cells in the pulmonary artery, thereby restricting blood flow.

Dr. Chung also found, working in collaboration with co-senior author, Robert S. Kass, PhD, the Alumni and David Hosack Professor of Pharmacology, chair of the department, and vice dean for research at CUMC, that the effects of the KCNK3 mutations could be reversed with an experimental phospholipase inhibitor called ONO-RS-082. The findings were made in cell cultures. Further study is needed to determine whether treatment with this or other drugs that affect potassium channels might be useful in the treatment of people with PAH, said Dr. Chung.

"KCNK3 mutations are a rare cause of PAH, so I don't want to oversell our findings," said Dr. Chung. "Still, it's exciting that we've found a mechanism that can lead to the disease that is a new, druggable target. It's also possible that targeting KCNK3 may be beneficial for patients who have PAH independent of their KCNK3 genetic status."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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The paper is titled, "A Novel Channelopathy in Pulmonary Arterial Hypertension." The other contributors are: Lijiang Ma, Danilo Roman-Campos, Eric D, Mélanie Eyries, Kevin Sampson, Florent Soubrier, Marine Germain, David-Alexandre Trégouët, Alain Borczuk, Erika Berman Rosenzweig, Barbara Girerd, David Montani, Marc Humbert, and James E. Loyd.

The authors declare no financial or other conflicts of interests.

The study was supported by grants from the National Institutes of Health (R01 HL060056, P01 HL072058, K23 HL098743, and R01 HL56810) and by a Vanderbilt Clinical and Translational Science Awards (UL1 RR024975) from the National Center for Research Resources.

Columbia University Medical Center

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'Study finds druggable target for pulmonary hypertension'

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