2013
Mechanisms Underlying Noise-Induced Tinnitus
Posted February 19, 2013
Thanos Tzounopoulos, Ph.D., University of Pittsburgh School of Medicine
Tinnitus, a debilitating condition most often caused by exposure to extreme sound, is the persistent perception of a sound in the absence of acoustic stimulus, commonly described as a "ringing of the ears." Tinnitus is almost universally experienced in some form, an estimated 5%-15% of the general population suffering chronically with this condition. Tinnitus has a significantly higher prevalence in war veterans, with a recent study showing that 49% of soldiers exposed to improvised explosive devices at the combat zone developed tinnitus. Despite the high prevalence and the debilitating effects of tinnitus, its pathophysiology is poorly understood and, as a result, there is no generally accepted cure, treatment, or prevention of this disorder. Currently, most approaches are focused on the management of tinnitus after it becomes a life-long disorder.
Dr. Thanos Tzounopoulos received a Fiscal Year 2009 Investigator-Initiated Research Award from the Peer Reviewed Medical Research Program to study the cellular mechanisms that trigger tinnitus. Dr. Tzounopoulos developed a mouse model of noise-induced tinnitus and an imaging technique to investigate the cellular mechanisms underlying the induction of tinnitus. He focused his studies on the dorsal cochlear nucleus (DCN), a brain region that is thought to be crucial for the induction of tinnitus. His studies revealed that DCN principal neurons in mice with behavioral evidence of tinnitus exhibited increased spontaneous firing activity - hyperexcitability - only in DCN regions that are more sensitive to high frequency sounds. The hyperexcitability was linked to sound-induced reduction of potassium channel activation. More significantly, pharmacological enhancement of potassium channel activity after exposure to noise significantly reduced the number of mice that develop tinnitus.
These promising results point to novel approaches for the development of drugs that could be used soon after the acoustic trauma to prevent the development of permanent and irreversible tinnitus.
Dr. Tzounopoulos plans to identify the critical period after noise exposure during which pharmacological manipulation is capable of preventing the development of tinnitus, and to develop more potent versions of drugs with minimal side effects.Publication:
Middleton JW, Kiritani T, Pedersen C, Turner J, Gordon M, Shepherd G, Tzounopoulos T. 2011. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity due to decreased GABAergic inhibition. Proc Natl Acad Sci U S A 108(18):76016
Links:
Public and Technical Abstracts: Mechanisms Underlying Noise-Induced Tinnitus
Cellular Therapy to Obtain Spine Fusion
Posted January 8, 2013
Elizabeth A. Olmsted-Davis, Ph.D., Baylor College of Medicine, Houston, Texas
Spinal conditions that lead to spine instability and bone degeneration are treated with spine fusion that requires invasive, painful surgery that involves stripping of the musculature, autologous bone grafts, and insertion of metal at the site of injury. Spinal fusion from these procedures can take as long as a year to achieve. Moreover, approximately 30% of the surgeries fail to produce spinal fusion due to inability of the fusion mass to adequately form and integrate with the pre-existing skeletal bone, which leads to significant pain.
Previous studies of human genetic disease have demonstrated that bone morphogenetic protein 2 (BMP2), a protein that plays an important role in the development of bone and cartilage, has the potential to rapidly form bone that can fuse into the skeleton. With support from a Fiscal Year 2006 Peer Reviewed Medical Research Program Advanced Technology: Product/Technology Down-Selection or Optimization Award, Dr. Elizabeth Olmsted-Davis and her colleagues Dr. Alan Davis and Dr. Jennifer West sought to test the hypothesis that sustained delivery of endogenously produced BMP2 at a target site could lead to rapid bone formation that would be capable of fusing with skeletal bone. This would provide a safe, efficacious system for inducing spine fusion that will eliminate the need of invasive surgery.
Dr. Olmsted-Davis and her team injected BMP2-producing cells encapsulated in a polyethylene diacrylate hydrogel (PEGDA) into the desired site in rodents, which led to rapid spinal fusions within 2 weeks. This non-surgical procedure is unique in several ways: (1) the BMP2 is endogenously produced in human cells at the specific location to mimic normal physiological levels, thus avoiding many of the adverse effects associated with high-dose delivery; (2) the BMP2-producing cells are encapsulated in hydrogels that permit free diffusion of BMP2, but prevents the cells from migrating away from the target location; (3) the encapsulation prevents immune detection and clearance of the cells and thus does not require cells from individual patients to be harvested and generated, but rather a single (allogenic) cell line can be used for manufacturing; (4) the microspheres can be injected multiple times to "tune" bone formation and spine fusion; (5) the materials can be specifically degraded during normal bone remodeling; (6) the cell line carries a "safety switch" that will allow physicians to instantly turn off bone formation, if needed, by delivery of a Food and Drug Administration (FDA)-approved small molecule; and (7) the osteoinductive microspheres can be cryopreserved and maintain efficacy, so that the system can be easily distributed for clinical use. Moreover, the system has significant versatility and has the potential to be useful in limb salvage and regeneration. Based on these promising results, Dr. Olmsted-Davis and her colleagues plan to refine this technique and generate preclinical data for FDA approval for use in humans.Selected Publications:
Olabisi RM, Lazard Z, Heggeness M, Moran KM, Hipp JA, Dewan A, Davis AR, West JL, and Olmsted-Davis EA. 2011. An injectable method for spine fusion. Spine J 11(6):545-546.
Hsu CW, Olabisi RM, Olmsted-Davis EA, Davis AR, and West JL. 2011. Cathepsin K-sensitive poly(ethylene glycol) hydrogels for degradation in response to bone resorption. J Biomed Mater Res A 98(1):53-62.
Olabisi RM, Lazard ZW, Hall MA, Kwon SK, Sevick-Muraca EM, Hipp JA, Davis AR, Olmsted-Davis EA, and West JL. 2010. Hydrogel microsphere encapsulation of a cell-based gene therapy system increases cell survival of injected cells, transgene expression, and bone volume in a model of heterotopic ossification. Tissue Eng Part A 16(12):3727-3736.
Links:
Public and Technical Abstracts: Cellular Therapy to Obtain Spine Fusion
