Applicants for the 1998 grants continued to be of the highest caliber. The Scientific Advisory Committee has done an admirable job of reviewing the proposals of these young neurosurgeons and has managed the difficult job of identifying the most outstanding applicants worthy of the financial support of the Research Foundation. A total of 39 applications were received, of which the following five individuals were awarded. We anticipate good results from their work.
Tord D. Alden, MD
1998 Research Fellow
University of Virginia
Sponsor: Gregory A. Helm, MD
Chairman: John A. Jane, MD, PhD
Research Title: Bone Morphogenetic Protein-2 Gene Therapy in Neurosurgery
Abstract: The overall aim of this proposal is to develop novel gene therapy strategies for improving the treatment of diseases that require spinal fusion. Numerous animal studies have demonstrated the efficacy of viral vectors for delivering therapeutic genes to many different tissues. However, the limitations of this approach include the utilization of viruses that have low transfection rates and the lack of tissue specific transgene expression. Traumatic fractures, lumbar stenosis, multiple cervical discectomy, tumors, degenerative processes, and congenital diseases are just a few examples where spinal fusion is utilized in neurosurgery. Recombinant human bone morphogenetic protein-2, an osteoinductive protein, has been shown in animal models to improve the fusion mass. The goal of this proposal will be to develop an efficient gene delivery system to express the BMP-2 gene using an adenoviral construct. The BMP-2 gene will then be placed under the control of the tissue specific osteocalcin promoter, which should target gene expression to osteoblasts.
Judith L. Gorelick, MD
1998 New York City Post-Graduate
Neurosurgery Course Research Fellow University of Michigan
Sponsor: Daniel S. Wechsler, MD
Chairman: Julian T. Hoff, MD
Research Title: The Role of the MXI1 Growth Suppressor Gene in the Pathogenesis of Glioblastoma Multiforme
Abstract: Malignant tumors of the brain and central nervous system are responsible for over 12,000 deaths per year in the United States, and of these tumors, glioblastomas multiforme is the most malignant and the most difficult to treat despite the use of aggressive multimodality therapy. Since it is currently well accepted that malignancy likely results from successive genetic alterations which lead to disordered control of cell growth, a better understanding of these mechanisms might suggest new approaches to therapy. MXI1 is a putative tumor suppressor gene, which maps to a region of chromosome 10 that is frequently involved in a significant proportion of human glioblastomas. To date, studies of the MXI1 gene have demonstrated frequent loss of heterozygosity (LOH) at the MXI1 locus and a reduction in growth rates of glioblastoma cell lines where MXI1 has been reintroduced in vitro. Through these studies, we hope to gain a deeper appreciation of the complexity of the mechanisms that modulate the function of MXI1, and to more fully understand the pathways to neoplasia.
James M. Schuster, MD
1998 Research Fellow
University of Washington/Seattle
Sponsor: Richard S. Morrison, MD
Chairman: H. Richard Winn, MD
Research Title: The Effects of Loss of p53 Function on Apoptotic Pathways in the Malignant Progression of Astrocytes
Abstract: Mutations of the p53 gene are among the most common genetic abberations in human tumors including CNS tumors. The loss of p53 mediated apoptosis (programmed cell death) can significantly enhance the survival of tumor cells and is associated with a more aggressive tumor phenotype. This investigation will determine if the loss of wild-type p53 function in serial passages of astrocytes derived from p53 (+-) mice results in changes in the expression of relevant cell death effectors, as well as the rate of spontaneous and stress induced apoptosis. We also will determine if increased expression of proapoptotic proteins introduced using an adenovirus vector will reduce in vitro growth and malignant transformation in p53 (–) astrocytes.
Frederick F. Lang, MD
1998 Rhone-Poulenc Rorer Young Clinician Investigator
MD Anderson Cancer Center
Sponsor and Chairman: Raymond Sawaya, MD
Research Title: Adenovirus-Mediated p53 Gene Transfer Combined with Ionizing Radiation and Antineoplastic Agents Against p53-Wild-Type Human Gliomas
Abstract: Transfer of the p53 gene using an adenovirus vector may be an effective alternative for treating gliomas, but current experience suggests that this type of gene therapy may have significant limitations as a single treatment modality because of the resistance of clones containing wild-type p53 alleles. Studies from our laboratory indicate that adenovirus-mediated p53 gene transfer into human glioma cell lines that contain wild-type p53 sensitizes the cells to ionizing radiation and to certain antineoplastic agents. The purpose of this proposal is to elucidate the biological mechanisms underlying the sensitizing action of combining adenovirus-mediated p53 gene transfer with radiation or chemotherapy, and to explore the therapeutic potential in vivo of combining p53 gene transfer with these modalities.
Carl Lauryssen, MD
1998 Shirley L. Bagan Young Clinician Investigator
Washington University/St. Louis
Sponsor: Jack R. Engsberg, MD
Chairman: Ralph G. Dacey, Jr, MD
Research Title: A Computer Analysis Outcome Study of Cervical Spondylotic Myelopathy
Abstract: The natural history of cervical spondylotic myelopathy is poorly understood, with up to 75 percent of patients showing progressive deterioration. The first aim of this study will use objective, quantitative computer generated measures, and a physical performance test, prior to, and following surgery to assess the effect of surgery on patients with cervical spondylotic myelopathy. The second aim is to determine if post-surgical functional outcomes can be predicted from pre-surgical, clinical, and diagnostic imaging measures. All patients will undergo pre-operative physical performance testing, diagnostic imaging, and computerized assessment of gait, spasticity, and strength. Post-operatively, three, six, and 12- month repeat testing will be performed to determine changes in functional outcome.