FY 1999/2000 Grant Process
Abstracts for 1999/2000 Grant Awards (July 1, 1999 to June 30, 2000)
#01-99 James BurgessLongwood College / Grant Title: DNA binding rates of platinum based anticancer drugs
Brief Summary: This research is aimed at the development of better anticancer drugs and is a collaborative effort by Longwood College, Virginia Commonwealth University-Massey Cancer Center, and the national Institute of Standards and Technology. Some of the most effective anticancer drugs kill cancerous tumor cells by damaging their DNA (genes). Many cancers, however, are insensitive to chemotherapeutic intervention (resistant to all of the currently used drugs). Excitingly, a new class of DNA damaging drugs has been developed that shows potent activity against a broad spectrum of cancers commonly resistant to current chemotherapeutic treatments. Human clinical trials are underway. An understanding of how these new drugs are able to kill cancer cells that are resistant to all other drugs is absolutely critical for optimizing their effectiveness. The speed at which these new drugs damage DNA is believed to be a vital characteristic that result in their excellent anticancer activity. However, there is no adequate method available for directly evaluating how quickly drugs damage DNA. Through collaboration with the National Institute of Standards and Technology, DNA based sensors have been developed at Longwood College to solve this problem. The DNA based sensor is electrically vibrated (on a molecular level) and, by tracking the vibration frequency of the sensor, it is possible to monitor the rates at which drugs damage DNA. The potential utility of this sensor has been demonstrated. It is hypothesized that the new drugs damage DNA (a region of a gene that suppresses cell death) faster than the most widely used anticancer drug.
#02-99 Daniel CoxUniversity of Virginia / Grant Title: Quantitative assessment of attention deficit/hyperactivity disorder: Validation of the EEG consistency index
Brief summary: Attention Deficit/Hyperactivity Disorder (ADHD) is the most common development disorder of childhood, affecting 3-5% of children in the United States, and often continuing in adulthood. ADHD is associated with multiple complications, including poor school achievement, substance abused automobile accidents, etc. Unfortunately, there is no objective procedure to diagnose and quantify ADHD. Consistent with the goals set by the 1998 NIH Consensus Statement on Diagnosis and Treatment of ADHD, we propose an inter-disciplinary, inter-institutional study that will test and validate with a large group of children the first physiologic diagnostic marker of ADHD – the Consistency Index (CI). The CI is based on our novel idea that ADHD interferes with cognitive transitions form one task to another and this interference can be measured through a biomathematical representation of electroencephalographic (EEG) data. In three small pilot studies the CI has been sensitive and specific to ADHD, has been reliable over three months, and has improved under the influence of Ritalin for ADHD males, but not controls.
To confirm and extend the clinical utility and the theoretical implications of the CI, we propose to college psychometric and EEG data from 20 boys and 20 girls with ADHD, ages, 8-11, and from 30 age/gender matched controls. Parallel to this data collection, we propose to further develop and validate optimal gender-specific mathematical models and methodological procedures. If successfully validated, this concept will shed light on the complex EEG manifestations of ADHD and will advocate a new ADHD diagnostic and assessment procedure.
#05-99 Russell FaustUniversity of Virginia / Grant Title: In-vivo indium-folate imaging of squalmous cell carcinoma of the head and neck
Brief summary: Receptors for normal nutrients (folate) are expressed on cell surfaces; some cancers express many times the normal number of these receptors. By coupling folate to a tracer that can be seen using special imaging detection equipment, we can detect where cancer cells are hiding, undetected by another means. Most cancers of the head and neck over-express this folate receptor. We propose to grow head and neck cancer cells as tumors in mice, then to image them by using folate coupled to Indium. In people with head and neck cancer, the ability to detect hidden cancer cells sooner than we are currently able to has the potential to double survival for these patients. The Commonwealth of Virginia has an unusually large number of people with head and neck cancer for its population size.
#07-99 Robert Granger IISweet Briar College / Grant Title: Synthesis and anticancer activity of novel platinum and palladium complexes
Brief summary: A newly synthesized class of transition metal complexes, comprised of pseudo-octahedrally bound bidentate diimene ligands on platinum (IV) or palladium (IV) metal centers, will be investigated for their application as useful DNA binding agents and their potential as anti-cancer agents in cell culture. Preliminary cell culture experiments with the first of these new diimene complexes have shown dramatic and unexpected cytotoxicity toward malignant cells of avian, mouse, and human origin.
Our versatile synthetic method will be applied to produce a series of novel Pt(IV) and Pd(IV) diimene complexes. We will determine the structure of the complexes via X-ray crystallography and explore their DNA binding and reduction chemistry. We will investigate the biological activity of these newly synthesized Pt(IV) and Pd(IV) diimene complexes in a variety of cultured cells, in order to determine: 1. Which of these new complexes show cytotoxic activity? 2. At what concentrations are the complexes active? 3. Is the cytotoxicity uniform or is there selective toxicity for malignant cell types? 4. What is the intracellular target (or targets) for the complexes? 5. What is the newly synthesized complexes against a panel of normal and malignant cell lines. We will also fractionate the cells and determine via NMR the oxidation state of the bound metal complexes and where in the cell the complexes concentrate. This project involves two PI’s, two collaborators and five summer undergraduate research assistants.
#06-99 Phillip HylemonVirginia Commonwealth University / Grant Title: Is cholesterol gallstones a bacterial disease?
Brief summary: More than 30 million Americans have cholesterol gallstones and more than 500,000 cholescystectomies (gallbladder removals) are performed each year. The propensity to develop cholesterol gallstones is complex and a number of risk factors have been noted that allow for predisposition to this disease, including: bile supersaturated with cholesterol; a decreased cholesterol nucleation time, and increased gallbladder mucin secretion. All of the listed risk factors are associated with an increased amount of deoxycholic acid in bile. Deoxychoic acid is derived from cholic acid in the colon by a small population of anaerobic bacteria. Hypothesis: Many cholesterol gallstone patients are colonized by high levels of intestinal bacteria that produce deoxycholic acid from cholic acid (7a-dehydroxylating). This leads to the enrichment of the bile with deoxycholic acid with increased risk for cholesterol gallstone formation. Objectives: 1) Determine the levels of 7a-dehydroxylating bacteria in cholesterol gallstone, pigmented gallstone, on control patients in Virginia (MCV and VA Hospitals); 2) Isolate, characterize, and identify, the kinds of 7a-dehydroxylating bacteria in cholesterol gallstone patients; 3) Clone, sequence, and analyze the bile acid inducible (bai) genes in selected 7a-dehydroxylating bacteria isolated form cholesterol gallstone patients. Develop DNA probes, using the isolated bai genes, which might be useful in detecting and quantify these bacteria in fecal samples.
#03-99 Geoffrey KrystalVirginia Commonwealth University / Grant Title: Inhibition of phyospatidylinositol-3 kinase as a novel therapeutic strategy for the treatment of small-cell lung cancer
Brief summary: Small cell lung cancer (SCLC) is a major health problem in the U.S. and Virginia and will be responsible for approximately 34,000 deaths nationwide this year. Despite the fact that SCLC is highly responsive to chemotherapy, with approximately one-third of patients attaining a complete clinical remission, 90-95% of patients relapse and die of their disease within two years. Increasing the doses of standard chemotherapeutic agents has increased toxicity without increasing the cure rate, underscoring the need for new therapeutic approaches. We have identified the phosphatidylinositol-3 kinase (P13K) pathway as a signal transduction pathway activated by several growth factors that mediate SCLC growth. Our current hypothesis is that activation of P13K pathway is absolutely necessary for SCLC growth and therefore strategies designed to inhibit this pathway could result in therapeutic benefit. The initial specific objective of this study will be to demonstrate whether highly specific strategies that inhibit P13K activity in cultured SCLC cell lines inhibit growth. The specific strategies that will e employed include an analysis of the effect of the prototypic P13K inhibitor Ly 294002 and its inactive chemical congener on SCLC growth. These results will be compared to those obtained when the P13K pathway is attenuated by molecular biologic means. We will also determine whether inhibition of the P13K by chemical or molecular biologic means will enhance response to standard chemotherapeutic agents. Finally, the downstream molecular mediators of P13K activity will be identified so that they too may become targets for novel drug development.
#04-99 George KunosVirginia Commonwealth University / Grant Title: Development of novel drugs for the treatment of high blood pressure
Brief summary: Inappropriate contraction of vascular smooth muscle narrows the lumen of arteries which can lead to elevated blood pressure or vascular disease such as coronary artery disease. The aim of treatment of such diseases is to dilate arteries. Although several types of vasodilator drugs are available, patients with vascular disease or high blood pressure are often resistant to existing vasodilator medication. Cannabinoids, the biologically active constituents of the marijuana plant, have been shown to lower blood pressure and dilate arteries in experimental animals, but their psychoactive properties make them unsuitable for the treatment of cardiovascular disease. In preliminary studies, we have found that the synthetic cannabinoid analog “abnormal cannabinoid” (abn-cbd) is devoid of psychoactive properties and does not bind to cannabinoid receptors in the brain. Yet, abn-cbd lowers blood pressure and dilates arteries in normal rats and mice, as well as in mice genetically deficient in the receptors that mediate the psychoactive effects of cannabinoids in the brain. This suggests that receptors mediating vasodilation by abn-cbd are different from cannabinoid receptors in the brain, and are thus suitable targets of vasodilator therapy. The purpose of the present proposal is to further characterize the cardiovascular effects of abn-cbd, and to develop structurally modified analogs of abn-cbd with improved vasodilator potency and efficacy. Such compounds may be useful in the treatment of high blood pressure or vascular disease.
#09-99 Richard MarconiVirginia Commonwealth University / Grant Title: Identification of conserved Borrelial antigens for use in the development of a new generation of Lyme disease diagnostic assays
Brief summary: Lyme disease is a tick transmitted disease that represents a serious public health concern. Lyme disease results from infection with various bacterial species that are classified in the genus Borrelia and which are members of the Borrelia burgdorferi sensu lato complex. If not diagnosed early, infection with the Lyme disease bacteria can lead to serious late stage complications that can be cardiac, neurological and/or musculoskeletal in nature. It has been difficult to determine the true incidence of Lyme disease in Virginia but evidence suggests that it is significantly underestimated. One reason for this is that available diagnostic assays are of low accuracy hence it is thought that many cases are not correctly diagnosed. The study proposed here seeks to develop a new generation of Lyme disease diagnostic assays with significantly improved accuracy. The development of these tests will result in more rapid diagnosis of Lyme disease, enhance our epidemiological understanding of this disease and lead to more appropriate treatment of individuals inflicted with other tick-borne infections. Clearly, such a test will be of great benefit to the residents of Virginia. The approach taken in this proposal is a thorough and systematic one that will exploit the recently determined B. burgdorferi genome sequence to identify proteins that can be reliably used as test substrates to detect infection with the Lyme disease bacteria.
#08-99 Birgit WintherUniversity of Virginia / Grant Title: Effects of common colds caused by viruses on middle-ear pressure in children