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Blocking an Enzyme with Multiple Affects on Asthma
Studies of the lungs of both mice and humans with asthma have shown an increase in an enzyme called arginase, which is present only in low levels in healthy lungs. The activity of this enzyme has multiple effects that make asthma worse, namely closing airways, increasing secretions in the lungs, and causing permanent scarring in airways. For these reasons, it is desirable to find drugs that block the activity of arginase. Dr. Christianson is seeking to do just this by determining the molecular structure of arginase and its complexes with inhibitors. This will allow him to develop drugs that bind to arginase and block its activity. The ultimate goal is to develop drugs that can be inhaled to prevent or reverse an attack of asthma. - David Christianson, Ph.D. University of Pennsylvania
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A New Approach to Block Airway Constriction in Asthma
In asthma, the muscles around the airways tighten, narrowing the passage for air to flow in and out of the lungs. This muscle contraction is activated when tiny holes, called “channels,” are opened on the surface of the muscles, allowing calcium to enter the cells. To block asthma, Dr. Clapham is seeking to block the entry of calcium into muscle through these channels. He has carefully identified the nature of the channels and is now designing drugs to block them. - David Clapham, M.D. Harvard Medical School and the Howard Hughes Medical Institute
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Finding the Shape Of Molecules that Promote Asthma
Attacks of asthma are launched and sustained by molecules called ‘cytokines’, which circulate through the body to activate the immune system. Cytokines bind to proteins on the surface of immune cells, signaling activity inside the cells that launch an immune attack. This attack is useful for defending against infections, but in asthma the response goes astray, causing unnecessary inflammation of the lungs and narrowing of the airways. To block this response in the lung, it would be useful to have drugs that prevent the cytokines from binding to immune cells in the lung. To this end, Dr. Garcia, is defining the exact shapes of molecules on the cell surface that can bind to cytokines. Knowing these shapes will enable chemists to design drugs that will block the binding by cytokines, arresting the immune responses that cause asthma. - K. Christopher Garcia, Ph.D. Stanford University
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Blocking Early Events that Activate Asthma
Dr. Holers studies the “complement system,” a cascade of enzymes in the blood that initiate an immune response to infection. Dr. Holers has shown that this cascade is activated early in asthma, causing an immune response even when no infection can be detected. By studying mice with asthma, Dr. Holers has shown that blocking the complement system can prevent asthma, and he has developed new approaches for doing this. The goal is to find methods that can be used in human asthma, allowing a new approach to therapy. - V. Michael Holers, M.D. University of Colorado
