Researchers develop blood test to detect membranous nephropathy

ScienceDaily (Nov. 30, 2011) — Research conducted by a pair of physicians at Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) has led to the development of a test that can help diagnose membranous nephropathy in its early stages. The test, which is currently only offered in the research setting and is awaiting commercial development, could have significant implications in the diagnosis and treatment of the disease. Currently, the only way to diagnose the disease is through a biopsy.

The pioneering work is being led by Laurence Beck, MD, PhD, assistant professor of medicine at BUSM and a nephrologist at BMC, and David Salant, MD, professor of medicine at BUSM and chief of the renal section at BMC.

Over the past four years, the Halpin Foundation has contributed more than $350,000 to Beck to investigate the genetics and molecular mechanisms behind membranous nephropathy. Most recently, Beck was awarded a $50,000 grant from the Foundation to further his efforts.

Membranous nephropathy is an autoimmune disease caused by the immune system attacking the kidneys, resulting in the thickening and dysfunction of the kidney's filters, called glomeruli. When antibodies attack the glomeruli, large amounts of protein in the urine are released. In 2009, Beck and Salant identified that the antibodies were binding to a protein in the glomeruli. They determined that the target was a protein called PLA2R, or phospholipase A2 receptor, and these findings were published in the New England Journal of Medicine.

"For the first time, a specific biomarker has been identified for this relatively common kidney disease," said Beck, who is part of an international collaboration that has demonstrated that these antibodies are present in patients from many different ethnicities.

With the antigen protein identified, Beck and Salant have developed a blood test to detect and measure the amount of the specific antibodies in a sample.

Approximately one third of patients with membranous nephropathy eventually develop kidney failure, requiring dialysis or a kidney transplant. According to the University of North Carolina's Kidney Center, the disease affects people over the age of 40, is rare in children and affects more men than women. This disease is treated by high powered chemotherapy, and if successful, the antibodies go away.

"Being able to detect the presence of these antibodies using a blood test has tremendous implications about who is treated, and for how long, with the often toxic immunosuppressive drugs," said Beck.

Beck continues his research focus on the treatment of the disease by targeting the antibodies and stopping them from attacking the glomeruli.

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The above story is reprinted from materials provided by Boston University Medical Center.

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Researchers examine role of inflammatory mechanisms in a healing heart

ScienceDaily (Nov. 30, 2011) — Virginia Commonwealth University researchers have found that an inflammatory mechanism known as inflammasome may lead to more damage in the heart following injury such as a heart attack, pointing researchers toward developing more targeted strategies to block the inflammatory mechanisms involved.

Following a heart attack, an inflammatory process occurs in the heart due to the lack of oxygen and nutrients. This process helps the heart to heal, but may also promote further damage to the heart. The mechanisms by which the heart responds to injury are not fully understood, so researchers have been examining the cellular pathways involved to gain further insight.

In a study published online the week of Nov. 21 in the Proceedings of the National Academy of Sciences, researchers addressed the role of a specific inflammatory mechanism, called inflammasome, during the process of healing in the heart. Using an animal model, the team found that inflammasome amplifies the response by generating the production of a key inflammatory mediator known as Interleukin-1ß. Further, they described that pharmacologic inhibition of the formation of inflammasome prevents heart enlargement and dysfunction.

"Defining the role of the inflammasome in the response to injury in the heart and the possibility to intervene opens a new area of investigation for the prevention and treatment of heart failure following a heart attack," said Antonio Abbate, M.D., assistant professor of medicine in the VCU Department of Internal Medicine and Division of Cardiology.

According to Abbate, who serves as the interim director for the cardiac intensive care unit at the VCU Pauley Heart Center, this study supports the team's previous findings that showed that Interleukin-1ß affects the heart, and blocking Interleukin-1ß benefits patients of heart attack and heart failure.

"Based on the findings of the current study we are even more convinced that blocking Interleukin-1ß may be safe and beneficial, and we are now exploring novel ways to do so," he said.

Abbate said there are four ongoing clinical trials at the VCU Pauley Heart Center in patients with various heart conditions treated with a drug called anakinra which blocks Interleukin-1ß.

Abbate and his team continue to examine the molecular mechanisms of inflammasome formation and heart injury, and hope to determine new ways to intervene with potentially more targeted strategies in the future.

The study was conducted in the Victoria W. Johnson Center for Research at VCU, which is directed by Norbert Voelkel, M.D, professor of medicine in the Pulmonary and Critical Care Division.

Abbate led with a multidisciplinary team of VCU researchers biologists, physicians, and pharmacists including Eleonora Mezzaroma, Ph.D., and Stefano Toldo, Ph.D., post-doctoral associates in the VCU Pauley Heart Center; Daniela Farkas, B.S., research specialist in the Victoria Johnson Research Laboratory; Benjamin Van Tassell, Pharm.D., assistant professor of pharmacology and outcome sciences; and Fadi Salloum, Ph.D., assistant professor of medicine and physiology in the VCU Pauley Heart Center.

This study was supported by a grant from the American Heart Association.

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Journal Reference:

E. Mezzaroma, S. Toldo, D. Farkas, I. M. Seropian, B. W. Van Tassell, F. N. Salloum, H. R. Kannan, A. C. Menna, N. F. Voelkel, A. Abbate. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1108586108

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Researchers build largest protein interaction map to date

ScienceDaily (Oct. 27, 2011) — Researchers have built a map that shows how thousands of proteins in a fruit fly cell communicate with each other. This is the largest and most detailed protein interaction map of a multicellular organism, demonstrating how approximately 5,000, or one third, of the proteins cooperate to keep life going.

"My group has been working for decades, trying to unravel the precise connections among the proteins and gain insight into how the cell functions as a whole," says Spyros Artavanis-Tsakonas, Harvard Medical School professor of cell biology and senior author on the paper. "For me, and hopefully researchers studying protein interactions, this map is a dream come true."

The study is published October 28 in the journal Cell.

While genes are a cell's data repository, containing all the instructions necessary for life, proteins are its labor force, talking to each other constantly and channeling vital information through vast and complicated networks to keep life stable and healthy. Humans and fruit flies are both descended from a common ancestor, and in most cases, both species still rely on the same ancient cellular machinery for survival. In that respect, the fruit fly's map serves as sort of a blueprint, a useful guide into the cellular activity of many higher organisms.

Understanding how proteins behave normally is often the key to their disease-causing behavior.

For this study, Artavanis-Tsakonas and his colleagues provide the first large-scale map of this population of proteins. Their map, which is not yet fully complete, reveals many of the relationships these myriad proteins make with each other as they collaborate, something which, to date, has been to a large degree an enduring mystery among biologists.

"We already know what approximately one-third of these proteins do," Artavanis-Tsakonas said. "For another third of them we can sort of guess. But there's another third that we know nothing about. And now through this kind of analysis we can begin to explore the functions of these proteins. This is giving us extraordinary insight into how the cell works."

One significant use for such a map is to assess how a cell responds to changes in metabolic conditions, such as interactions with drugs or in conditions where genetic alterations occur. Finding such answers might lead to future drug treatments for disease, and perhaps to a deeper understanding of what occurs in conditions such as cancer.

"This is of extraordinary translational value," Artavanis-Tsakonas said. "In order to know how the proteins work you must know who they talk to. And then you can examine whether a disease somehow alters this conversation."

A pivotal part of this research involved a scientific technique called mass spectrometry, which is relatively new to the science of biology. The ultra-precise mass spectrometry experiments were done by HMS professor of cell biology Steven Gygi. Mass spectrometry is used to measure the exact weight (the mass) and thus identify each individual protein in a sample. It is a technique originally devised by physicists for analyzing atomic particles. But in recent years mass spectrometry was adapted and refined for new and powerful uses in basic biological research. Other studies using similar techniques to date have focused on small groups of related proteins or single celled model organisms such as bacteria and yeast.

Despite the huge amount already known about the fruit fly and its genetic endowment, much about the function of thousands of proteins remains a mystery. This map, however, now gives us precise clues about their function. Filling in the detailed protein map can help scientists gain important insights into the process of development, that is, how a creature is put together, maintained and operated.

"Our analyses also sheds light on how proteins and protein networks have evolved in different animals," said K. G. Guruharsha, a postdoctoral fellow in Artavanis-Tsakonas's lab and a first author on the paper.

Co-lead authors on the paper included Jean-Francois Rual, also a postdoctoral fellow in Artavanis-Tsakonas's lab, and Julian Mintseris and Bo Zhai, both research fellows in Gygi's lab.

Also important in this effort was the work of K. VijayRaghavan, at the National Centre for Biological Sciences in Bangalore, India. Similarly, crucial contributions to this work also came from the University of California, in Berkeley, where Susan E. Celniker collaborated through her studies in the fruit fly genome center.

This research was funded by the National Institutes of Health.

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The above story is reprinted from materials provided by Harvard Medical School. The original article was written by Robert Cooke.

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