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| Scientists identify protein required to regrow injured nerves in limbs Posted: 19 Jun 2012 09:00 PM PDT A protein required to regrow injured peripheral nerves has been identified by researchers at Washington University School of Medicine in St. Louis. The finding, in mice, has implications for improving recovery after nerve injury in the extremities. It also opens new avenues of investigation toward triggering nerve regeneration in the central nervous system, notorious for its inability to heal.
Peripheral nerves provide the sense of touch and drive the muscles that move arms and legs, hands and feet. Unlike nerves of the central nervous system, peripheral nerves can regenerate after they are cut or crushed. But the mechanisms behind the regeneration are not well understood. In the new study, published online June 20 in Neuron, the scientists show that a protein called dual leucine zipper kinase (DLK) regulates signals that tell the nerve cell it has been injured ? often communicating over distances of several feet. The protein governs whether the neuron turns on its regeneration program. “DLK is a key molecule linking an injury to the nerve’s response to that injury, allowing the nerve to regenerate,” says Aaron DiAntonio, MD, PhD, professor of developmental biology. “How does an injured nerve know that it is injured? How does it take that information and turn on a regenerative program and regrow connections? And why does only the peripheral nervous system respond this way, while the central nervous system does not? We think DLK is part of the answer.” The nerve cell body containing the nucleus or “brain” of a peripheral nerve resides in the spinal cord. During early development, these nerves send long, thin, branching wires, called axons, out to the tips of the fingers and toes. Once the axons reach their targets (a muscle, for example), they stop extending and remain mostly unchanged for the life of the organism. Unless they’re damaged. If an axon is severed somewhere between the cell body in the spinal cord and the muscle, the piece of axon that is no longer connected to the cell body begins to disintegrate. Earlier work showed that DLK helps regulate this axonal degeneration. And in worms and flies, DLK also is known to govern the formation of an axon’s growth cone, the structure responsible for extending the tip of a growing axon whether after injury or during development. The formation of the growth cone is an important part of the early, local response of a nerve to injury. But a later response, traveling over greater distances, proves vital for relaying the signals that activate genes promoting regeneration. This late response can happen hours or even days after injury. But in mice, unlike worms and flies, DiAntonio and his colleagues found that DLK is not involved in an axon’s early response to injury. Even without DLK, the growth cone forms. But a lack of DLK means the nerve cell body, nestled in the spinal cord far from the injury, doesn’t get the message that it’s injured. Without the signals relaying the injury message, the cell body doesn’t turn on its regeneration program and the growth cone’s progress in extending the axon stalls. In addition, it was shown many years ago that axons regrow faster after a second injury than axons injured only once. In other words, injury itself increases an axon’s ability to regenerate. Furthering this work, first author Jung Eun Shin, graduate research assistant, and her colleagues found that DLK is required to promote this accelerated growth. “A neuron that has seen a previous injury now has a different regenerative program than one that has never been damaged,” Shin says. “We hope to be able to identify what is different between these two neurons ? specifically what factors lead to the improved regeneration after a second injury. We have found that activated DLK is one such factor. We would like to activate DLK in a newly injured neuron to see if it has improved regeneration.” In addition to speeding peripheral nerve recovery, DiAntonio and Shin see possible implications in the central nervous system. It is known for example, that some of the important factors regulated and ramped up by DLK are not activated in the central nervous system. “Since this sort of signaling doesn’t appear to happen in the central nervous system, it’s possible these nerves don’t ‘know’ when they are injured,” DiAntonio says. “It’s an exciting idea ? but not at all proven ? that activating DLK in the central nervous system could promote its regeneration.” ### Shin JE, Cho Y, Beirowski B, Milbrandt J, Cavalli V, DiAntonio A. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron. Online June 20, 2012. This work was supported by the National Institutes of Health (NIH) Neuroscience Blueprint Center Core Grant (P30 NS057105) to Washington University, the HOPE Center for Neurological Disorders, the European Molecular Biology Organization (EMBO) long-term fellowship, the Edward Mallinckrodt Jr. Foundation, and NIH grants NS060709, AG13730, NS070053 and NS065053. Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare. Contact: Julia Evangelou Strait |
| New drugs, new ways to target androgens in prostate cancer therapy Posted: 19 Jun 2012 09:00 PM PDT Prostate cancer cells require androgens including testosterone to grow. A recent review in the British Journal of Urology International describes new classes of drugs that target androgens in novel ways, providing alternatives to the traditional methods that frequently carry high side effects.
“In many ways, therapies for prostate cancer have led the way in the fight against the disease,” says E. David Crawford, MD, investigator at the University of Colorado Cancer Center and review co-author. “The first effective oral therapy for any cancer was estrogen which was described in 1941. The first cancer biomarker that allowed diagnosis and staging was prostatic acid phosphatase back in 1938. Then there was little progress for over four decades.” During those 40 years, in which early work in prostate cancer led to Nobel prizes for researchers Charles Huggins and Andrew Schally, other cancer types capitalized on this research, notably developing hormone therapies targeting estrogen in breast cancer. But work in prostate cancer stalled. “What we realized is that production of androgens like testosterone depends on an intact system in which the brain recognizes hormone levels, signals the pituitary to increase or decrease production, and the pituitary in turn sets the testes in motion. Additionally, by targeting the production of androgens by the testes, we could break that system at many other points,” Crawford says. For example, estrogen is similar enough to testosterone that administering estrogen to patients tricked the brain into thinking testosterone hormone levels were high ? with high presumed hormone levels, the brain sent no production signal to the pituitary. But estrogen therapy led to side effects including breast enlargement. The next class of drugs, known as luteinizing hormone releasing hormones or LHRHs, intervened in this signaling chain at the level of the pituitary. Just as estrogen keeps the brain from signaling for more testosterone, LHRHs keep the pituitary from passing messages to the testes. “Because the effects of LHRHs are reversible, this allowed us to use hormone-targeting therapies much earlier in the disease,” Crawford says. “But LHRHs lead to an initial spike in testosterone, before it decreases.” Most patients can withstand this spike, but for some, for example those with bone metastasis in the back, a spike in testosterone could flare the disease and lead to spinal complications. “It was only about ten years ago that somebody was able to make a usable antagonist,” Crawford says. Instead of first spiking and then lowering testosterone, these LHRH antagonists lead to an immediate drop. And instead of targeting the signaling pathway that leads to the production of androgens including testosterone, androgen antagonists like Enzalutamide (formerly known as MDV3100), currently in phase III clinical trials, target cells’ ability to trap testosterone that exists in the body ? it doesn’t matter how much testosterone is floating around, as long as prostate cancer cells are unable to grab it. Specifically, Enzalutamide and other androgen antagonists are easier to “catch” than the androgens themselves, and so cells grab Enzalutamide and are then unable to grab testosterone. Also new to the field are drugs that block the production of androgens from all sources which of course includes the testes, but also includes blocking the smaller amounts produced by the adrenals and even by the cancer itself. This class of drugs is called androgen biosynthesis inhibitors, and the first approved is a drug called abiraterone or Zytiga. “Targeting cells’ androgen receptors is a new and exciting development in the field of prostate cancer therapy,” Crawford says. “As these new drugs make their way from the lab to clinic, we expect the ability to offer androgen antagonists to patients whose cancers have resisted other treatments.” ### Dr. Crawford wishes to disclose that he is an advisor to the company Medivation, which manufactures the drug Enzolutamide. Contact: Erika Matich |
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