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duminică, 5 august 2012

A Better Understanding Of Rhomboid Proteases May Lead To New Therapies For Malaria And Other Parasitic Diseases

Johns Hopkins scientists have decoded for the first time the "stability blueprint" of an enzyme that resides in a cell's membrane, mapping which parts of the enzyme are important for its shape and function. These studies, published in advance online in Structure and in Nature Chemical Biology, could eventually lead to the development of drugs to treat malaria and other parasitic diseases.

"[It's] the first time we really understand the architectural logic behind the structure of the enzyme," says Sinisa Urban, Ph.D., an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and an investigator at the Howard Hughes Medical Institute, who with his team has unlocked the mysteries of a special class of enzymes called rhomboid proteases.

Rhomboid proteases are present in many different organisms, and are a unique type of enzyme that resides in the cell's membrane where they cut proteins. Previously Urban and his colleagues demonstrated that the rhomboid enzyme is critical for Plasmodium falciparum, the parasite that causes malaria, to successfully invade red blood cells, a step that ultimately leads to infection. Urban says understanding the stability of rhomboid protease shape may impact the design of enzyme inhibitors - potential drugs. "These enzymes have no selective inhibitors," says Urban. "We really need to understand how [the enzyme] works - is it as stiff as a rock, or is it more gummy, like Jell-O?"

One challenge of studying rhomboid enzymes is that they are surrounded by membranes, making them more difficult to manipulate and work with. To address this, Urban's research team turned to a technique known as thermal light scattering, which heats enzyme samples to progressively higher temperatures while measuring the amount of light bouncing back off of the molecules. Enzymes that have broken from their normal shape will scatter light differently, and the temperature at which this occurs (in effect, the breaking point of the enzyme) indicates the inherent stability of the enzyme.

The researchers first precisely measured the stability of the rhomboid enzyme from E. coli bacteria. Surprisingly, says Urban, the rhomboid enzyme was more "Jell-O-like" than other membrane proteins with similar shapes. He guesses that this "jiggly shape" may help rhomboid proteases interact with other proteins that it cuts. To find which parts of the enzyme are most important for maintaining shape and which parts are more crucial for function, the researchers then made and tested 150 differently altered versions of the enzyme. They found four main regions important for maintaining shape and at least two regions important for function.

The researchers also took advantage of computer simulations to test their ideas about how the enzyme functions. Using a computer program model of the enzyme, they programmed in features of its natural membrane environment, which consists mostly of fats and is very limited in water. The computer program then simulated how this environment might influence the enzyme. Researchers found that the enzyme contains a special internal pocket for holding water molecules - a great advantage in its natural, water-limiting environment.

"We're very excited about our findings and are especially curious about the versions of the enzyme that lost function despite no obvious change in stability or shape," says Urban. Ultimately he hopes that a better understanding of rhomboid proteases will lead to new therapies for treating malaria and other parasitic diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our tropical diseases section for the latest news on this subject. These studies were supported by the Howard Hughes Medical Institute, a National Institute of General Medical Sciences grant (GM079223), a National Institute of Allergy and Infectious Diseases grant (AI066025), the National Science Foundation (NSF) and the David and Lucile Packard Foundation.
Other researchers who participated in this study include Rosanna Baker, Yanzi Zhou, Syed Moin and Yingkai Zhang.
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marți, 13 decembrie 2011

Researchers Say Scar Findings Could Lead To New Therapies

Main Category: Dermatology
Also Included In: Immune System / Vaccines
Article Date: 13 Dec 2011 - 0:00 PST

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Researchers at the Stanford University School of Medicine report that they have identified the molecular pathway through which physical force contributes to scarring in mice.

"Our study exposes one of the fundamental mechanisms by which the mechanical environment can directly increase inflammation, which is strongly implicated in scarring," said Geoffrey Gurtner, MD, professor and associate chair of surgery.

Mice genetically engineered to lack an enzyme that is activated by mechanical force demonstrated less inflammation and fibrosis - the formation of excess fibrous connective tissue - in their incisions than mice in a control group, the study found. Inflammation and scar formation also were reduced among mice injected with an organic compound, a small molecule called PF-573228, that blocks this enzyme, which helps cells sense changes in the mechanical environment.

While further testing is needed to determine the validity of the findings in humans, the researchers say they hope their work will pave the way for new treatments of fibrotic diseases - disorders caused by excess scarring, such as pulmonary fibrosis (the buildup of scar tissue in the lungs) - as well as inflammatory diseases, such as rheumatoid arthritis.

The study was published online in Nature Medicine. Gurtner is the senior author. The lead author is postdoctoral scholar Victor Wong, MD.

Inflammation, an important part of healing, occurs when white blood cells and the chemicals they release try to kill bacteria and eat up damaged tissue at the site of an injury. However, inflammation is also linked to scarring. Excessive scarring is known as fibrosis. And while there are chemical mechanisms that lead to inflammation, mechanical forces generally have been overlooked as a key stimulator of this biological response and as a possible therapeutic target, the researchers say. An example of such a force would be the pulling on an incision when a patient moves; it's the reason stitches are sometimes needed.

"We just haven't taken the physical environment - the environment of mechanical forces that hold all our cells together - seriously enough as a source of inflammation and fibrosis," Gurtner said.

Previous studies have implicated the enzyme, known as focal adhesion kinase, in cellular responses to force, but whether it played a role in inflammation and scarring remained unclear. When the researchers had it genetically engineered out of mice for the current study, incisions in those mice healed normally but scarring was markedly diminished. Ten days after the mice sustained a skin incision, 48 percent fewer scar-tissue cells had formed around it compared with incisions in a control group, according to the study.

The researchers found that the enzyme appears to modulate protein molecules often used by cells to communicate with one another. In test tube studies, mouse scar tissue missing the enzyme did not respond normally to mechanical stimuli and released far lower levels of inflammatory mediators.

The researchers also tested the effects of the enzyme-inhibiting molecule (PF-573228) on human cells that play a key role in wound healing and found that the molecules that stimulate inflammation were not released.

Tests on humans are needed before researchers can evaluate whether this approach could serve as the basis for a valid therapy. The researchers said they hope their findings can eventually be used to develop treatments for diseases that involve excess scarring throughout the body. "These results suggest that targeted strategies to uncouple mechanical force from inflammation and fibrosis may prove clinically successful across diverse organ systems," they concluded.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our dermatology section for the latest news on this subject. Other Stanford co-authors were Michael Longaker, MD, MBA, the Deane P. and Louise Mitchell Professor at the School of Medicine; Satoshi Akaishi, MD, a visiting surgeon from Japan; postdoctoral fellows Michael Sorkin, MD, Kemal Levi, MD, and Jason Glotzbach, MD; bioinformatics student Michael Januszyk, MD; and medical students Emily Nelson, Kristine Rustad, Josemaria Paterno and Ivan Vial.
The study was funded by grants from the Armed Forces Institute of Regenerative Medicine and the Oak Foundation. Information about Stanford's Department of Surgery, which also supported the work, is available at http://surgery.stanford.edu.
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vineri, 9 decembrie 2011

Potential New Therapies For People With Declining Sense Of Smell

Main Category: Ear, Nose and Throat
Also Included In: Seniors / Aging; Neurology / Neuroscience; Genetics
Article Date: 09 Dec 2011 - 1:00 PST

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University of California, Berkeley, neuroscientists have discovered a genetic trigger that makes the nose renew its smell sensors, providing hope for new therapies for people who have lost their sense of smell due to trauma or old age.

The gene tells olfactory stem cells the adult tissue stem cells in the nose to mature into the sensory neurons that detect odors and relay that information to the brain.

"Anosmia the absence of smell is a vastly underappreciated public health problem in our aging population. Many people lose the will to eat, which can lead to malnutrition, because the ability to taste depends on our sense of smell, which often declines with age," said lead researcher and campus neuroscientist John Ngai.

"One reason may be that as a person ages, the olfactory stem cells age and are less able to replace mature cells, or maybe they are just depleted," he said. "So, if we had a way to promote active stem cell self-renewal, we might be better able to replace these lost cells and maintain sensory function."

Gary K. Beauchamp, director of the Monell Chemical Senses Center in Philadelphia, who was not a member of the research team, noted that the olfactory system stands out for its ability to regenerate following injury or certain diseases

"This new paper ... presents an elegant analysis of some of the underlying genetic mechanisms regulating this regeneration," Beauchamp said. "It also provides important insights that should eventually allow clinicians to enhance regeneration, induce it in cases where, for currently unknown reasons, olfactory loss appears permanent, or even prevent functional loss as a person ages."

The discovery may also help scientists harness olfactory stem cells and stem cells found in other sensory systems more generally, to recover sensory function following injury or degenerative disease, said Ngai, the Coates Family Professor of Neuroscience in UC Berkeley's Department of Molecular and Cell Biology and director of the Helen Wills Neuroscience Institute and the QB3 Functional Genomics Laboratory.

Ngai, post-doctoral fellow Russell B. Fletcher and their UC Berkeley colleagues report their findings in the journal Neuron.

Self-renewal or differentiation

In the nose, smell sensory neurons live only about 30 days, then are replaced by new cells. The new cells are generated by adult stem cells in the olfactory epithelium. A key question, Ngai said, is what tells the stem cells to divide into new ones a process called self-renewal or to mature, or differentiate, into fully functional sensory nerve cells and other cells critical to maintaining olfactory function.

"These stem cells are capable of reconstituting the entire sensory epithelium of the nose following injury," Ngai said, "so understanding how these stem cells work is important for understanding the regeneration process that goes on in the nose."

Fletcher and Ngai screened nose epithelial cells for regulatory genes and discovered one, called p63, that was a previously known transcription factor that acts by controlling the transcription of other regulatory genes in epithelial stem cells, such as those in the skin, the lining of the airways and the prostate. By knocking out the p63 gene in mice, they showed that nasal olfactory stem cells rapidly differentiated into sensory neurons at the expense of the stem cells themselves.

"This gene produces a molecule that is like a brake on the stem cell," Fletcher said. "When the brake is on, stem cells self-renew. If you remove the brake, the stem cells go into differentiation."

A drug that regulates p63, or modulates one of the genes that p63, in turn, regulates, might be able to boost the number of nasal stem cells as well as the number that mature into smell neurons.

Because p63 is found in many epithelial tissues, Ngai noted, these findings could be applied to other adult tissue stem cells including stem cells in the skin and possibly lead to future therapeutic "cell replacement" strategies to take the place of damaged or dead cells not only in the nervous system but in other epihelial tissues in the body.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our ear, nose and throat section for the latest news on this subject. Coauthors with Ngai and Russell are former graduate student Melanie S. Prasol, graduate student Jose Estrada, staff professionals Ariane Baudhuin and Yoon Gi Choi, and the late Karen Vranizan of UC Berkeley's Functional Genomics Laboratory.
The research is funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health, UC Berkeley's Siebel Stem Cell Institute, the California Institute of Regenerative Medicine and the National Science Foundation.
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