SPAR, a program of the American Asthma Foundation, awards grants to investigators who are pursuing new, breakthrough pathways for treating, preventing, and curing asthma.
SPAR SENIOR INVESTIGATIVE AWARDS
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Mark E Anderson, M.D., Ph.D.
Calmodulin Kinase Signaling in Asthma
University of Iowa
Dr. Anderson is an expert in calmodulin kinase, an enzyme found in heart muscle. He plans to study this enzyme in airway muscles. Preliminary evidence suggests that this enzyme may control the growth of airway muscle, which releases signals that promote inflammation. If this proves to be the case, Dr. Anderson has developed experimental drugs that can inhibit this pathway, potentially reducing airway muscle growth and inflammation.
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Jonathan Chernoff, M.D., Ph.D.
P21-Activated Kinase-1 in Asthma
Fox Chase Cancer Center
Many cell proteins become active when they are modified by the attachment of a phosphate molecule through enzymes called phosphokinases. Dr. Chernoff is an expert in the study of these enzymes. He discovered that one of these enzymes, PAK-1, is expressed in a subset of white blood cells involved in asthma. These mast cells (white blood cells) contribute to constriction of airways, inflammation, and secretion of mucus. In preliminary studies, Dr. Chernoff has shown that loss of PAK-1 reduces the ability of mast cells to release the signals that promote asthma. He proposes that blocking PAK-1 may be useful in treating asthma. He plans to study the functions of PAK-1 mast cells, and to test inhibitors of PAK-1 for their effects on mast cell function.
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Peter Cresswell, Ph.D.
Redux Regulation of Inflammatory Response in Asthma
Yale University
Dr. Cresswell is one of the nation's leading investigators in inflammation and immunology. When inflammation occurs in the lung (or elsewhere), damage occurs in part due to the generation of reactive oxygen. Reactive oxygen is useful in killing bacteria and other infections, but it can harm normal tissue. As a precaution, the body produces enzymes, called reductases, which disarm the reactive oxygen. He will examine the role of a particular reductase in asthma, and notes that reactive oxygen may alter the function of immune cells without killing them. Reductases may not only protect immune cells, but also regulate their function and their contribution to asthma.
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Eric Gouaux, Ph.D.
Structure of P2X Receptor Ion Channels in Asthma and Inflammation
Oregon Health and Science University
Inflammatory cells have molecules on their surface that signal cells to activate and/or migrate. Some of these molecules, called P2X receptors, bind to small molecules released when other cells die. There is evidence to suggest that P2X receptors play an important role in inflammatory diseases like asthma, but there are currently no therapies that involve P2Y receptors. Dr. Gouaux will define the structure of P2X receptors, and will use the structure of the receptors to develop drugs that inhibit their activity.
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Marshall Horwitz, M.D., Ph.D.
Eosinophil Photoresponse and Circadian Triggers in Asthma
University of Washington
Asthma is usually worse at night. Eosinophils, white blood cells important in asthma, also rise at night. Dr. Horwitz cites evidence that levels of eosinophils are, in part, regulated by light. He also finds that eosinophils have molecules that absorb light, and thereby may alter cell function. He will attempt to identify these molecules and to test the role of light in regulating eosinophil function, and he will relate these phenomena to the effects of light on asthma.
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Lily Jan, Ph.D.
Targeting Calcium-Activated Chloride Channel (CaCC) in Asthma
University of California, San Francisco
Asthma causes lung inflammation, constriction and thickening of airways, and an increase in the production of airway mucus, a thick liquid that leads to death by drowning in severe asthma. The production of mucus is regulated by changes in the flow of chloride ions, through highly regulated channels in the membrane of mucus-producing cells. Dr. Jan has identified the gene responsible for one such channel called the Calcium-activated Chloride Channel (CaCC), and she proposes that this channel provides a central mechanism for regulation of mucus production in asthma. Dr. Jan will test and screen for compounds that block the CaCC, contributing to both basic research and potential therapies for asthma.
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John Kearney, Ph.D.
Modulation of Allergic Asthma by B Cells and Antibodies
University of Alabama at Birmingham
The rise of asthma's prevalence in the industrialized world is correlated with a decrease in early life exposure to bacteria. Dr. Kearney proposes that specific bacteria, which have specific carbohydrates (sugar) on their surface, are important in protecting against asthma. He hypothesizes that early exposure to these bacteria initiates immunity against all organisms expressing this carbohydrate, and will thus protect against asthma. Although asthma is an immune disease, there is little research into the role of antibodies against sugars on organisms that are inhaled.
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Bruce Klein, M.D.
The Chitin Receptor in Asthma Pathogenesis
University of Wisconsin-Madison
Chitin is a complex sugar abundant in nature, where it is found in cell walls of fungi and exoskeletons of insects. Chitin appears to play a major role in asthma; it drives the immune system toward responses typical in asthma. Despite this link between chitin and asthma, receptors that recognize chitin and thereby alter the immune response have not been identified. Dr. Klein, an expert in immune response to fungi, will attempt to identify these receptors, and to determine their contribution to asthma in mice.
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Victor Nizet, M.D.
HIF Regulation of Innate Immune and Inflammatory Responses in Asthma
University of California, San Diego
In severe asthma, airway constriction obstructs airflow, depriving lung and immune cells of oxygen through the bloodstream. Dr. Nizet will study the effects of oxygen deprivation on both lung and blood cells, focusing on a molecule that regulates a broad array of genes. This molecule, called "hypoxia-inducible transcription factor" (HIF), plays a central role in the control of inflammation and immunity. Dr. Nizet will study the effects of HIF in asthma by testing drugs that block HIF in mice.
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Kodi Ravichandran, B.V.Sc., Ph.D.
Epithelial Homeostasis, Apoptotic Cell Clearance in Asthma
University of Virginia
Dr. Ravichandran is a leading expert in the body's removal of damaged cells, which are traditionally believed to be digested by macrophages. Dr. Ravichandran proposes that cells lining the airways are engulfed by neighboring lining cells when they are ready to be replaced. This is important, since the process of digesting other cells circumvents inflammation provoked by cell death. Thus, failure of airway lining cells to properly remove neighboring cells could set the stage for asthma. Dr. Ravichandran will study animal and human cell models to test his hypothesis.
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Kenneth Rock, M.D.
Cell-Injury-Induced Sterile Inflammatory Pathways in Asthma
University of Massachusetts Medical School
Dr. Rock is a prominent immunologist whose work has demonstrated the role of dying cells in inflammation. He has identified molecules released by dying cells, and he will test the resulting effects of these molecules on inflammatory cells. Dr. Rock hypothesizes that airway injury caused by cell death promotes inflammation, setting the stage for asthma. This may provide a therapeutic target by interrupting both the initiation and maintenance of asthma.
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Bert Semler, Ph.D.
Identification of a Novel Anti-Viral Target for a Respiratory Tract Pathogen
University of California, Irvine
The common cold is caused by rhinoviruses, which are known to worsen asthma. Dr. Semler proposes a new approach to treating rhinoviral infection by identifying and blocking enzymes important for survival of the virus. There is a broad need for such a therapy, but the benefit to asthmatics is of particular importance. The approach has an excellent scientific basis.
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Satish Srivastava, Ph.D.
Aldose Reductase Inhibition in Asthma
The University of Texas Medical Branch at Galveston
Dr. Srivastava is a prominent investigator in the study of diabetes. His research has shown that high levels of glucose in diabetes promote inflammation in blood vessels, contributing to the clinical consequences of diabetes, and that inflammation can be prevented by blocking an enzyme called aldose reductase. In preliminary studies, Dr. Srivastava has shown that blocking this enzyme reduces inflammation in animals with asthma. Because of its importance in glucose metabolism, there are considerable efforts to develop drugs that will inhibit aldose reductase.
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Gregory Verdine, Ph.D.
Semisynthetically Modified IL-13 Analogs as Novel Biologics in Asthma Treatment
Harvard University
Interleukin-13 (IL-13) is a molecule produced during inflammation and that is of known importance in asthma. In the absence of IL-13, mice are resistant to asthma. Despite many attempts, however, effective methods for sustained blocking of IL-13 in human asthma have not been developed. Dr. Verdine will chemically modify IL- 13, using a method he has pioneered, making the molecule more stable and more likely to bind to its receptor, in a manner rendering the receptor inactive. Thus, this modified, inactive IL-13 would replace the normal IL-13, blocking its effect. This research was made possible by the studies of another SPAR Award recipient, Chris Garcia, who demonstrated the structure of IL-13 when bound to its receptors.
SPAR EARLY EXCELLENCE AWARDS
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Matthew Bogyo, Ph.D.
Cysteine Cathepsins in the Disease Pathology of Asthma
Stanford University
Inflammatory cells damage the lung through the release of enzymes that break down proteins. Dr. Bogyo proposes that airway damage in asthma may be mediated by enzymes of this type, especially a group of enzymes called cysteine cathepsins. He has studied the role of these enzymes in cancer, and he now proposes to do so in asthma. His approaches include blocking these enzymes in animal models, a method for which he is developing new drugs. Thus, in testing the importance of cysteine cathepsins in asthma, Dr. Bogyo will pursue new approaches in treatment.
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Jeffrey Rathmell, Ph.D.
Lymphocyte Metabolism as a Modulator and Therapeutic Target in Asthma
Duke University
With Craig Thompson, Dr. Rathmell helped to define the importance of glucose metabolism in the regulation of immunity, and he continues to lead in this field. Like all cells, immune and inflammatory cells derive energy from sugar (glucose). Dr. Rathmell will study the metabolism of glucose by immune cells in asthma, including the examination of drugs that alter glucose metabolism. Dr. Rathmell will apply his work to asthma and the fundamental links between asthma and obesity. His research will address how the immune system obtains energy to mediate an immune response, and how the respective energy source is altered in asthma.
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Jennifer Whistler, Ph.D.
Trafficking Profiles of NPSR/GPR154 in Asthma Pathogenesis
Ernest Gallo Clinic and Research Center, University of California, San Francisco
Cells communicate and adapt by binding through receptor molecules on the cell surface, which bind to external molecules, and then transmitting the resulting signals back to the cell. These signals may cause a muscle cell to contract, or may signal an immune cell to destroy an infection. Brain cells have receptors that control thought and movement, among other functions. Dr. Whistler has studied brain cell receptors in drug addiction. One of these receptors, NPSR/GPR154, is widely expressed in the body, and was shown to be frequently altered in patients with asthma. Dr. Whistler will study the function of this receptor in the airways, and she will define the consequences of its alteration in association with asthma.
