Quinn Eastman

Emory/Georgia Tech: partners in creating heart valve repair devices

Vinod Thourani, associate professor of cardiac surgery at Emory School of Medicine, along with Jorge Jimenez and Ajit Yoganathan, biomedical engineers at Georgia Tech and Emory, have been teaming up to invent new devices for making heart valve repair easier.

At the Georgia Bio and Atlanta Clinical and Translational Science Institute’s second annual conference on academic/industry partnerships, Thourani described how he and his colleagues developed technology that is now being commercialized.

Apica Cardiovascular co-founders (l-r) James Greene, Vinod Thourani, Jorge Jimenez and Ajit Yoganathan

Apica Cardiovascular was founded based on technology invented by Jimenez, Thourani, Yoganathan and Thomas Vassiliades, a former Emory surgeon.

Thourani is associate director of the Structural Heart Program at Emory.

Yoganathan is director of the Cardiovascular Fluid Mechanics Laboratory at Georgia Tech and the Center for Innovative Cardiovascular Technologies.

The technology simplifies and standardizes a technique for accessing the heart via the apex, the tip of the heart’s cone pointing down and to the left. This allows a surgeon to enter the heart, deliver devices such as heart valves or left ventricular assist devices, and get out again, all without loss of blood or sutures.

Schematic of transapical aortic valve implantation. The prosthesis is implanted within the native annulus by balloon inflation.

At the conference, Thourani recalled that the idea for the device came when he described a particularly difficult surgical case to Jimenez.  Thourani said that a principal motivation for the device came for the need to prevent bleeding after the valve repair procedure is completed.

With research and development support from the Coulter Foundation Translational Research Program and the Georgia Research Alliance VentureLab program, the company has already completed a series of pre-clinical studies to test the functionality of their device and its biocompatibility.

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Brain chemical linked to migraines could be anxiety target

Neuroscientist Michael Davis, PhD, and his colleagues have devoted years to mapping out the parts of the brain responsible for driving fear and anxiety. In a recent review article, they describe the differences between fear and anxiety in this way:

Fear is a generally adaptive state of apprehension that begins rapidly and dissipates quickly once the threat is removed (phasic fear). Anxiety is elicited by less specific and less predictable threats, or by those that are physically or psychologically more distant (sustained fear).

Michael Davis is an investigator at Yerkes National Primate Research Center and Emory School of Medicine

A host of their studies suggest that one part of the brain, the amygdala, is instrumental in producing “phasic fear,” while the bed nucleus of the stria terminalis (BNST) is important for “sustained fear.”

In a new report in the Journal of Neuroscience, Davis’ team describes the effects of a brain communication chemical, which is known primarily for its role in driving migraine headaches, in enhancing anxiety.

“This is the first study to show a role of this peptide, in a brain area we’ve identified as being important for anxiety.  This could lead to new drug targets to selectively reduce anxiety,” Davis says.

His team found that introducing calcitonin gene-related peptide (CGRP) into rats’ BNSTs can increase the anxiety they experience from loud noises or light, in that they startle more and avoid well-lit places. This peptide appears to activate other parts of the brain including the amygdala, hypothalamus and brainstem, producing fear-related symptoms.

Slice of rat brain showing the bed nucleus of the stria terminalis (BNST) and the central amygdala (Ce)

If Davis and his colleagues block CGRP’s function by introducing a short, decoy version of CGRP into the BNST, the reverse does not happen: the rats are not more relaxed. However, the short version does block the startle-enhancing effects of a smelly chemical produced by foxes that scientists use to heighten anxiety-like behavior in rats. This suggests that interfering with CGRP can reduce fear-related symptoms in situations where the rats are already under stress.

“Blockade of CGRP receptors may thus represent a novel therapeutic target for the treatment of stress-induced anxiety and related psychopathologies such as post-traumatic stress disorder,” says the paper’s first author, postdoctoral fellow Kelly Sink.

In fact, experimental drugs that work against CGRP are already in clinical trials to treat migraine headaches. But first, Sink reports that she and her colleagues are examining the relationship between CGRP and the stress hormone CRF (corticotropin-releasing factor) — another target of pharmacological interest — in the parts of the brain important for fear responses.

Posted on by Quinn Eastman in Neuro 1 Comment

Another avenue of HIV trickery reveals opportunity

Emory and University of Rochester researchers have discovered an extra way by which HIV adapts to survive in a hiding spot in the human immune system. The results are published in the Journal of Biological Chemistry.

A team led by Baek Kim from the University of Rochester and Raymond Schinazi from Emory found that when HIV faces a shortage of the building blocks it usually uses to replicate, the virus adapts by using different building blocks. The discovery may offer scientists a new way to try to stop the virus.

One of HIV’s favorite hiding spots is an immune cell called a macrophage, whose job is to chew up and destroy foreign invaders and cellular debris. One can think of macrophages as worker bees: they don’t reproduce because they’re focused on getting stuff done.

Raymond Schinazi, PhD, DSc, is director of the Laboratory of Biochemical Pharmacology at Emory's Center for AIDS Research

Normally, HIV uses “dNTPs” (building blocks of DNA), but dNTPs are found at very low levels in macrophages because they’ve stopped dividing and making new DNA. Current drugs generally target dNTPs, and aim at the infection in a different type of cells: T cells.

Macrophages do have high levels of RNA building blocks (“rNTPs”). The team found that HIV uses primarily rNTPs instead of dNTPs to replicate inside macrophages. When the team blocked the ability of the virus to interact with rNTPs, its ability to replicate in macrophages was cut by more than 90 percent.

“The first cells that HIV infects in the genital tract are non-dividing target cell types such as macrophages,” Kim says. “Current drugs were developed to be effective only when the infection has already moved beyond these cells. Perhaps we can use this information to help create a microbicide to stop the virus or limit its activity much earlier.”

Compounds that interfere with the use of rNTPs already exist and have been tested as anti-cancer drugs.

“We are now developing new anti-HIV drugs jointly based on this novel approach that are essentially non-toxic and can be used to treat and prevent HIV infections,” Schinazi says.

Baek Kim, PhD

The first authors of the paper are graduate students Edward Kennedy from Rochester and Christina Gavegnano from Emory. Other authors include graduate students Laura Nguyen, Rebecca Slate and Amanda Lucas from Rochester, and postdoc Emilie Fromentin from Emory.

The research was funded by the National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs.

University of Rochester press release

Posted on by Quinn Eastman in Immunology 1 Comment

Reassuring news on viral immunity + HIV vaccine

A recent paper in Journal of Immunology suggests that a platform for an HIV vaccine developed by Yerkes National Primate Research Center scientists won’t run into the same problems as another HIV vaccine. Postdoc Sunil Kannanganat is the first author of the JI paper, with Emory Vaccine Center researcher Rama Amara as senior author.

Harriet Robinson, MD and Rama Rao Amara, PhD

Many HIV vaccines have been built by putting genes from HIV into the backbone of another virus. Some have used a modified cold virus (adenovirus 5). The vaccine developed at Yerkes uses modified vaccinia Ankara (MVA), a relative of smallpox and chicken pox.

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Challenges in islet transplantation

Two recent research papers from the Emory Transplant Center describe research on pancreatic islet transplantation, an experimental procedure that could help people with type I diabetes live without daily insulin injections.

Islet transplantation may offer people with type I diabetes the ability to produce their own insulin again

As with other types of transplantation, the challenge with islet transplantation is to avoid rejection of the donated organ and to balance that goal against side effects from the drugs needed to control the immune system. These papers illustrate how that balancing act is especially complex.

In the last decade, transplant specialists developed a method for islet transplantation named the “Edmonton protocol” after pioneers at the University of Alberta. While the emergence of this method was a major step forward, there are limitations:

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Secrets of the elite: Effective immune control of HIV

A small minority of individuals infected with HIV — about one in 300 – are naturally able to suppress viral replication with their immune systems, and can keep HIV levels extremely low for years. Doctors have named these individuals “elite controllers.”

“These individuals have naturally achieved the outcome sought by HIV vaccine researchers worldwide.  Studying them will ultimately inform the design of a more effective HIV vaccine,” says Vincent Marconi, a physician-scientist at Grady Health System’s Infectious Disease Clinic on Ponce de Leon and an associate professor in the Emory School of Medicine.

Vincent Marconi, MD

Marconi is a co-author (along with investigators at over 200 institutions) on a genomics study of elite controllers published Thursday in Science Express. Led by Bruce Walker at Massachusetts General Hospital and Paul de Bakker at the Broad Institute and Brigham and Women’s Hospital in Boston, the team of researchers scanned through the genomes of close to 1,000 elite controllers and 2,600 people with progressive HIV infection. They identified several sites linked with immune control of HIV, all in a region encoding HLA proteins.

HLA proteins play key roles in activating T cell immunity, and are also necessary for the development of T cells. They grab onto segments of proteins, called peptides, inside the cell and carry them to the cell membrane. In the right context, certain viral peptides can mark infected cells for destruction by “killer” T cells.

Previously, MGH/MIT researchers theorized that people with certain forms of their HLA genes develop T cells with a restricted repertoire, yet broader activity. Their T cells would be more likely to still recognize HIV when the virus mutates. A drawback is that these individuals may have a higher risk for developing autoimmune diseases. The theory is described in more detail in this Nature News article.

Marconi is continuing his part of this research into what makes elite controllers’ immune systems special, which he began at the Department of Defense Infectious Disease Clinical Research Program, in collaboration with Eric Hunter, co-director of Emory’s Center for AIDS Research, and research associate Ling Yue at Emory Vaccine Center. The research is supported by the Center for AIDS Research and the National Institute of Allergy and Infectious Diseases.

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A path to treatment of lymphedema

Lymphedema, or swelling because of the impaired flow of lymph fluid, can occur as a consequence of cancer or cancer treatment. Chemotherapy can damage lymph ducts, and often surgeons remove lymph nodes that may be affected by cancer metastasis. Lymphedema can result in painful swelling, impaired mobility and changes in appearance.

Young-sup Yoon, MD, PhD

Emory scientists, led by cardiologist and stem cell biologist Young-sup Yoon, have shown that they can isolate progenitor cells for the lining of lymph ducts. This finding could lead to doctors being able to regenerate and repair lymph ducts using a patient’s own cells. The results are described in a paper published recently in the journal Circulation.

The authors used the cell surface marker podoplanin as a handle for isolating the progenitor cells from bone marrow. Previous research has demonstrated that podoplanin is essential for the development of the lymphatic system.
In the paper, the authors use several animal models to show that the progenitor cells could contribute to the formation of new lymph ducts, both by becoming part of the lymph ducts and by stimulating the growth of nearby cells.

“This lymphatic vessel–forming capability can be used for the treatment of lymphedema or chronic unhealed wounds,” Yoon says.

Isolated lymphatic endothelial cells (red) incorporate into lymph ducts (green) in a model of wound healing in mice.

The authors also show that mice with tumors show an increase in the number of this type of circulating progenitor cells. This suggests that tumors send out signals that encourage lymph duct growth – a parallel to the well-known ability of tumors to drive growth of blood vessels nearby. Yoon says the presence of these cells could be a marker for tumor growth and metastasis. Because tumors often metastasize along lymph ducts and into lymph nodes, studying this type of cells could lead to new targets for blocking tumor metastasis.

A recent review in the journal Genes & Development summarizes additional functions of the lymphatic system in fat metabolism, obesity, inflammation, and the regulation of salt storage in hypertension.

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Adjuvants: once immunologists’ “dirty little secret”

Two presentations on Emory research at last week’s AIDS Vaccine 2010 conference concerned adjuvants. These are substances that act as amplifiers, stimulating the immune system while keeping its focus on the specific components of a vaccine.

Charlie Janeway (1943-2003)

Immunologist Charlie Janeway once described adjuvants as immunology’s “dirty little secret,” because for a long time scientists did not know how they worked. Some adjuvants can sound irritating and nasty, such as alum and oil emulsion. Alum is the only vaccine adjuvant now licensed for human clinical use in the US. Over the last few years, scientists have learned that adjuvants rev up what is now known as the “innate immune system,” so that the body knows that the vaccine is something foreign and dangerous.

Rama Rao Amara, a vaccine researcher at Emory Vaccine Center and Yerkes National Primate Research Center, and Harriet Robinson, former head of microbiology and immunology at Yerkes and now chief scientific officer at the firm GeoVax, both described extra ingredients for the DNA/MVA vaccine that Robinson designed while at Yerkes in collaboration with NIH researchers.

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What if HIV was just another virus

Imagine that HIV was a “normal” virus. An infection begins and the body responds, without getting trapped in a cycle where CD4+ T cells are consumed and the immune system is crippled.

SIV can infect sooty mangabeys but it doesn't cripple their immune systems.

The attractiveness of this idea explains some of why scientists are interested in sooty mangabeys and other non-human primates. HIV’s relative SIV can infect them, but they usually don’t develop immunodeficiency.

At last week’s AIDS Vaccine 2010 conference, Cynthia Derdeyn reported her laboratory’s recent results investigating sooty mangabeys, which don’t develop high levels of neutralizing antibodies against SIV when infected. Derdeyn’s group at Emory Vaccine Center and Yerkes National Primate Research Center studies how HIV and SIV evade the immune system.

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