After initial success with pioneering procedures developed by this department to attempt primary closure of myelomeningoceles in utero, this project is the next step in refining this technique. It addresses the question of timing for in utero repair of neural tube defects by characterizing the toxic effects of human amniotic fluid on the unprotected fetal rat spinal cord in cell culture. This model has shown that at [24 weeks] of gestation, amniotic fluid exerts a maximal toxic effect on embryonic spinal cord cells, and therefore dictates consideration as to timing of in utero repair of humans with prenatally diagnosed myelomeningocele defects.
Of pride to the Department is the fact that Dr. Michael Drewek has won a national award for his part in this research as a resident interested in pediatric neurosurgery. He received this award after presenting his results at the American Association of Neurological Surgeons Meeting in Philadelphia last fall.
Title: Investigation of an amino acid kinase, KGX, as a tumor suppressor factor in glioma transformation
Principle Investigator: Dr. Steven Toms
Co-investigators: Jennifer Pietenpol, Ph.D., Dept. of Toxicology, Vanderbilt University, Bryan R. G. Williams, Ph.D., Chairman, Department of Cancer Biology, The Cleveland Clinic Foundation
KGX is an 814 amino acid kinase which maps to human chromosome 10q24, the area of the highest loss of heterozygosity for glioblastoma multiforme (GBM) as well as prostate cancer. The kinase exhibits homology with other human mitogen activated protein kinases as well as kinases in yeast and Drosophila. In vitro kinase assays using recombinant KGX exhibit strong kinase activity versus histone and myelin basic protein. Yeast two-hybrid assays revealed TAFII31 to be a potential binding partner. In vitro binding assays have confirmed this relationship as well as the binding relationship between KGX and p53. Transient transfections of KGX into NIH3T3 cells have confirmed that over-expression of KGX and KGX mutants alter the transcription of a p53 dependent reporter construct.
Investigation is currently underway in three areas:
We hope to determine within the next year if KGX is, in fact, a tumor suppresser and the exact nature of its relationship with p53. Future studies with this gene will center on its role in cell cycle its role in the response to radiation and other DNA damaging agents, as well as its role in other malignancies.
Title: Investigation of the free electron laser in peripheral nerve welding in rats
Principle Investigator: Dr. Peter Konrad
Co-investigator: Dr. Duco Jansen, Department of Biomedical Engineering
Fixed wavelength lasers have been tried unsuccessfully in the past to "weld" peripheral nerves together for repair of damaged segments or transected nerves. A key point in the failure of this technique has been the failure to maintain tensile strength in the initial post-operative recovery period. A unique advantage is the minimal scar tissue produced by laser assisted annealing of perineural proteins during the welding process. Recent advances in the development of "biological soldering compounds" may provide a solution to the problem with tensile strength. Potentially, the free electron laser may reveal a unique wavelength which can optimize coaptation of fascicles within the peripheral nerve as well as maximize strength after welding to provide optimal functional recovery of damaged peripheral nerves. Translation of this research into surgery on humans at the Free Electron Laser Facility is a paramount goal of this project.
Title: Optical detection of functional activity in neural tissue
Principle Investigator: Dr. Peter Konrad
Co-investigator: Dr. Anita Mahadaven-Jansen, Department of Biomedical Engineering
Recent advances in fiber optic detection and transmission have allowed accurate and high-resolution imaging of the nervous system to occur across a broad spectrum of wavelengths. Research at several center have revealed the capability to "see" electrophysiological activity at a cellular and tissue level. This project attempts to investigate the acquisition of images of natural or evoked electrical activity of the brain, spinal cord, and/or peripheral nerves in animal models and humans. Critical to the practical application of this technique is the ability to acquire such functional images in real time without the administration of electrically coupled dyes. Based on other work by Dr. Mahadaven-Jansen, we feel that this is feasible with enhanced imaging techniques trained to observe bio-fluorescence. Ultimately, such techniques would provide visual, real-time feedback to neurosurgeons operating in areas of the nervous system in which critical functions are to be preserved or ablated. This is a natural extension of image guided neurosurgery.