Since 1983, the Neurosurgery Re-search and Education Foundation has funded 31 Research Fellowships and 29 Young Clinician Investigator Awards. With these grants, some of the nation’s most promising neurosurgeons have begun their research careers. The awards have been made possible through the generosity of AANS members, corporations, foundations and interested individuals. This year, the Scientific Advisory Committee of the Research Foundation reviewed 38 applications and approved five for grants. Funding for the following individual researchers began in July.
2000 Research Fellow
Dean Chou, MD
John Hopkins Hospital
Sponsor: Robert Benezra, MD
Chairman: Donlin Long, MD, PhD
Title: “Inhibition of Angiogenesis by Knockout of Id1 and Id3 and its Effects on Murine Brain Tumor Growth”
Inhibition of angiogenesis at the genetic level by knockout has been shown to inhibit xenograft lymphoma and breast tumor growth; the project will investigate brain tumor growth after the inhibition of angiogenesis. Inhibition of xenograft tumor growth has been inhibited via knockout of the genes Id1 and Id3, which target helix-loop-helix transcription factors. Reduction of Id dosage results in an angiogenic defect, which blocks the vasularization, growth, and metastasis of tumor xenografts. A murine brain tumor model is produced after transgenic modificiation to express TVA, an avian surface cell receptor. These cells are transfected with an avian viral vector that contains dominant negative tumor suppressor genes or oncogenes. We propose to breed these mice to the knockout model for Id1 and Id3 (thereby inhibiting angiogenesis) to assess whether inhibition of angiogenesis will prevent growth of brain tumors (compared to controls).
Also, the project can study xenograft brain tumors in this model and explore the different angiogenic processes in xenografts versus tumors in situ. The -clinical consequence of the results (positive or negative) will direct further investigation in pharmacologic or gene therapy against angiogenesis in the treatment of brain tumors.
2000 American Brain Tumor Young Clinician Investigator
John K. Park, MD, PhD
Brigham & Women’s Hospital
Sponsor & Chairman: Peter McL. Black, MD
Title: “Prevention of Venous Thromboembolism in Brain Tumor Patients”
Deep venous thrombosis (DVT) and pulmonary embolism (PE) can be catastrophic complications for brain tumor patients following craniotomy. In 1995-96, 497 brain tumor patients underwent craniotomies at Brigham and Women’s Hospital. Despite the routine use of low dose, unfractionated heparin and pneumatic compression boots, the clinically documented rate of DVT was 10%. Further analysis of this figure revealed a 7.5% rate for primary brain tumor patients and a 19% rate for metastatic brain tumor patients. Based on preliminary data, there is a clear need to develop a more effective therapeutic strategy for the prevention of DVTs as well as PEs. The use of low molecular heparins is increasing in other fields of medicine. To determine if these fractionated forms of heparin are both safe and effective in preventing DVTs in post craniotomy patients, a clinical trial is proposed.
2000 Hunt-Wilson Young Clinician Investigator
Bruce E. Pollock, MD
Mayo Clinic
Sponsor: Michael J. Ebersold, MD
Chairman: David G. Piepgras, MD
Title: “Patient Outcomes after Vestibular Schwannoma Management:
A Prospective Comparison of Surgical Resection and
Sterotactic Radiosurgery”
The preferred management of patients with vestibular schwannomas (acoustic neuromas) is controversial. Over the past several decades, advances in anesthesia, neuroradiology and microsurgery have led to significant improvements in patient outcomes after vestibular schwannoma resection. As a less invasive alternative to surgical resection, stereotactic radiosurgery has been utilized increasingly over the past 10 years. Currently, no study is available that meets the requirements of evidence-based medical practice to conclude that either surgical resection or stereotactic radiosurgery should be the preferred management strategy for patients diagnosed with small- to medium-sized vestibular schwannomas. Each year between 45 and 50 patients with vestibular schwannomas are operated on at the Mayo Clinic. Assuming 25 patients who undergo surgical resection annually would be candidates for radiosurgery, sample size analysis (power=0.8, significance level= 0.05) predicts that patient accrual over three years is likely to detect significant differences in outcomes between the patient groups. The specific factors to be compared would include facial nerve function, hearing function, management-related complications, tumor recurrence/growth control, sub-jective symptoms and employment/ activities of daily living. All the data will be prospectively gathered and blinded evaluations performed by individuals independent of surgical teams.
2000 Young Clinician Investigator
Michael A. Vogelbaum, MD, PhD
Cleveland Clinic Foundation
Sponsor: John Cowell, PhD
Chairman: Marc Mayberg, MD
Title: “Mechanisms by Which P53 Regulates Bax-Induced Apoptosis in Human Gliomas”
Development of neoplasms and resistance of cancer cells to clinical treatment with DNA-damaging modalities is in part due to the loss of ability of cells to undergo apoptosis. Further understanding of the key mechanisms underlying DNA-damage induced apoptosis will lead to novel therapies. Overexpression of wild type p53 in human malignant glioma cell lines results in transactivation of the pro-apoptotic gene bax and spontaneous apoptosis in cells with mutant p53, but not in those with wild type p53. However, the same p53 mutant cell lines can support high levels of bax overexpression alone, in the absence of wild-type p53 overexpressions. In contrast, bax overexpression in p53 wild-type cell lines produces spontaneous apoptosis. It appears that both functional P53 and elevated bax levels must be present for apoptosis to occur. One explanation for the requirement of wild-type P53 for bax -induced apoptosis is that P53 mediates a “death signal” distinct from its transactivation of bax. We will demonstrate more clearly that bax over-expression in-duced apoptosis requires the presence of functional P53, demonstrating this requirement is present in tumor cells obtained from O.R., and identify successful strategies for determining substrate(s) for a separate “death signal” pathway transduced by P53.
2000 Codman/DePuy AcroMed/Johnson & Johnson Research Fellow
Michael M. Woodruff, MD
University of Utah Medical Center
Sponsor: Robert Gross, MD
Chairman: Peter Heilbrun, MD
Title:“Neural Restoration after Radiation Injury”
Apoptosis has recently been shown to play a role in early radiation-induced brain injury. Post-radiation apoptosis has been observed in the subependymal region, which contains a population of multipotent precursor cells that maintain the ability to proliferate and migrate throughout adulthood. Depletion of this active population of cells may underlie the late degenerative changes seen in white matter after irradiation. Since experimentally induced apoptosis of cortical neurons in the mouse triggers the expression of a set of neurotrophic factors that supports the differentiation and integration of grafted neural stem cells, the irradiated subependymal zone (SEZ) may, through a similar mechanism, support growth of transplanted neural cells. We will analyze the expression of developmentally relevant neurotrophic factors by the irradiated rat brain. Using neural transplantation as a tool to elucidate the cellular and molecular mechanisms underlying the response of the SEZ to radiation injury, we will characterize the ability of transplanted SEZ stem cells to
- differentiate and integrate into the apoptotic microenviroment,
- prevent late degeneration of white matter characteristic of radiation injury, and
- ameliorate the behavioral changes associated with radiation-induced brain injury.
Gifts from Estates, Neurosurgical Groups and Foundations
- Estate of Lester Mount
- Estate of Virginia Van Sant Reeves
Neurosurgical Group Supporters
- Georgetown University, Department of Neurosurgery
- University of Pittsburgh, Department of Neurosurgery
University of Wisconsin Medical Foundation
- Neurosurgical Specialists, in honor of Edward Benzel, MD
- Foundation Gifts
- Friedman/Grossman Family Foundation/Robert G. Grossman, MD
- Sam & Jennie Rovit Memorial Foundation, Inc.
- Berman Family Philanthropic Fund
- Andrew B. & Lynn Kaufman Philanthropic Fund