The Research Foundation of the AANS continues to support the long-term growth and survival of neurosurgery by providing start-up funding for clinical research. Following are five researchers recently selected by the Foundation’s Scientific Advisory Committee to receive grants for their work in neuroscience research.
1999 Rhone-Poulenc Rorer Research Fellow
Gregory D. Foltz, MD
University of Washington
Chair: H. Richard Winn, MD
Sponsors: Leroy Hood, MD, and Richard Morrison, MD
Research Title: High Density cDNA Array Analysis of Gene Expression in Astrocytic Tumors.
Abstract: The goal of this research is to characterize gene expression changes associated with malignant transformation in astrocytes. Malignant gliomas are the most common primary tumors in the CNS in adults and, unfortunately, have poor outcome despite aggressive treatment. Mutations and deletions of the p53 gene occur in 30-50 percent of low and high-grade gliomas suggesting its role in astrocytes malignant transformation. Recent advances in molecular biotechnology have produced tools capable of analyzing gene expression changes on a comprehensive scale at distinct time points in a biological process. Applying these tools to the study of neoplastic transformation in astrocytes after the loss of wild-type p53 function will provide insight into the critical determinants of apoptosis and tumor progression in malignant gliomas.
1999 Shirley L. Bagan Research Fellow
Babak S. Jahromi, MD
University of Toronto
Chair: Charles H. Tator, MD, PhD
Sponsor: Bryce K.A. Weir, MD
Research Title: Electrophysiological Properties and Intracellular Ca2+ Homeostasis in Vasospastic Smooth Muscle.
Abstract: Removal of blood from the subarachnoid space of monkeys within three days of hemorrhage causes vasospasm to resolve four days later. However, if blood is removed after five days from hemorrhage, vasospasm does not resolve within four days. Rather, it persists with the same severity as it does in animals without clot removal. This phase of clot-independent vasospasm is transient because vasospasm eventually resolves 14 days after the hemorrhage. What changes occur in the smooth muscle cells that first prevent, and then allow, relaxation? What is the mechanism of development of those changes? We hypothesize that blood alters smooth muscle cells in cerebral arteries so they remain contracted even in the absence of an ongoing stimulus. They then relax regardless of the presence of spasmogens. We propose to study vasospastic smooth muscle cells using electrophysiological techniques and calcium microfluorimetry to define what these alterations are and to gain insight into the mechanism(s) by which the above-noted features of vasospasm occur.
1999 Research Fellow
Sunghoon Lee, MD
Yale University
Chair: Dennis D. Spencer, MD
Sponsor: Anne Williamson, MD
Research Title: Long-term Modifications in the Human Hippocampus: Implications for Human Memory.
Abstract: Long-term potential (LTP) and long-term depression (LTD) are forms of synaptic plasticity that have been proposed as the cellular foundation for memory and associative learning. Significant energy and resources have been devoted to the investigation of the fundamental mechanisms of LTP and LTD. However, the question still remains unanswered as to whether LTP and LTD have been documented in the human hippocampus. We propose to perform LTP and LTD experiments in the human hippocampus that is resected as part of the surgical therapy for medically intractable epilepsy. We will perform a series of experiments to test the hypothesis that LTP and LTD occur in the human hippocampus and to define their physiological and pharmacological parameters. Lastly, we hope to compare the patient’s pre-operative in vivo memory function with the degree of synaptic plasticity found in vitro following resection.
1999 New York City Post-Graduate Neurosurgery Course Young Clinician Investigator
Robert E. Gross, MD
University of Utah
Chair: M. Peter Heilbrun, MD
Sponsor: Mark Nobel, MD
Research Title: Role of Netrins in the Generation and Regeneration of the Nigrostriatal Pathway.
Abstract: The reconstruction of neural pathways has the potential for restoring neurological function in a variety of neurodegenerative diseases, including Parkinson’s Disease. Neural reconstruction has been limited by sparse knowledge of growth-promoting and growth-inhibiting molecules that play a role in normal pathway development. These experiments will examine the role of the netrins, a new family of ligands with growth-promoting and chemotropic activity in the spinal cord and brainstem, in the ontogeny of the nigrostriatal and striatoniagral pathways. The effects of netrins on differentiation and neurite outgrowth of striatal and nigral precursors will be examined, and the expression of netrins and their receptors will be explored. These experiments should provide insights into ways to manipulate netrin signaling for pathway reconstruction in animal models of Parkinson’s and Huntington’s Disease.
1999 Young Clinician Investigator
John H. Sampson, MD
Duke University
Chair: Allan H. Friedman, MD
Sponsor: Darell Bigner, MD, PhD
Research Title: Determination of the Radiopharmacokinetics and Dose for Bulk Flow Microinfusion of 131-I-Labeled Antitenascin Monoclonal Antibody.
Abstract: Direct injection of I-labeled anti-tenascin monoclonal antibodies (MAbs) into closed surgically-created brain tumor resection cavities at our institution has produced promising Phase I and Phase II results with significant post-treatment median survival times of >60 weeks in patients with recurrent malignant brain tumors. Still, the majority of patients with malignant brain tumors remain ineligible for such therapy because their tumors are not safely resectable or a closed cavity cannot be created during the resection. Based on preclinical and clinical data from our laboratory and others, we hypothesize that the application of targeted radiotherapy delivered by MAbs that recognize an epitope specific to tumor cells within the intracerebral compartment can be expanded and improved by the use of 1) Bulk flow microinfusion to optimize penetration into tumor and surrounding brain infiltrated by tumor; 2) “humanized” MAbs to increase biostability and retention time within the tumor; and 3) more potent radioisotopes with higher linear energy transfer (LET), such as At, that have a relative biological effectiveness significantly greater than low LET b-emitters like I to increase tumor cell killing. To test these hypotheses, we seek to define the pharmacokinetics of intratumoral bulk flow microinfusion within the context of Phase I trials of I- and At-labeled anti-tenascin MAbs.