Since 2000 the American Asthma Foundation Research Program has awarded over $100 million to support innovative research in asthma. In doing so, the Program has significantly advanced the field of asthma research.
Listed below are 36 scientists whose AAF-sponsored research has led to major advances in understanding and/or treating asthma.
Michael R. Blackburn, Ph.D.
2000 Junior Award
University of Texas Health Sciences Center at Houston
Using a Drug Necessary for Immunity to Help Asthma
A genetic cause of immune deficiency in children is the lack of an enzyme called adenosine deaminase (ADA), and patients lacking ADA can be treated by replacing the enzyme. Dr. Blackburn has found that treatment with ADA unexpectedly reduces lung inflammation in animal models for asthma by reducing levels of adenosine, one of the targets of the ADA enzyme. Dr. Blackburn’s AAF-sponsored studies also led him to define a molecule on the surface of cells that binds to adenosine, and this has provided a new target for the treatment of asthma. Based on his work, major pharmaceutical companies are testing a new drug for the treatment of asthma.
Richard A. Bond, Ph.D.
2003 Junior Award
University of Houston
Turning the Treatment of Asthma on its Head
Many patients with asthma inhale drugs called ‘β-agonists’, such as albuterol, which open the airways. Drugs called ‘β-blockers’ oppose the action of β-agonists. Although β-blockers have long been used for diseases such as hypertension, they are usually forbidden in patients with asthma because they may make asthma worse. From his studies of animals however, Dr. Bond has surprising evidence that this may not be true in the long run; asthma may instead improve with low daily doses of β-blockers. Based on Dr. Bond’s studies, the NIH is now supporting the testing of beta-blockers in patients with asthma. If this works as it does in animals, it will turn the treatment of asthma on its head—small doses of what was once thought a ‘poison’ in asthma will instead be used to treat it.
David W. Christianson, Ph.D.
2006 Senior Award
University of Pennsylvania
Blocking an Enzyme with Multiple Effects on Asthma
The lungs of both mice and humans with asthma have 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. Christiansen has done this. At present the drug is being tested in other diseases, but it remains a possible therapy for asthma.
David E. Clapham, M.D., Ph.D.
2004 Senior Award
Children’s Hospital, Boston
Preventing the Airway Muscles from Squeezing the Airways During Asthma Attacks
The sudden difficulty in breathing that occurs in asthma is due to muscles around the airways, which tighten and squeeze the airways. This muscle tightening requires the entry of calcium into muscle from the surrounding tissues. Dr. Clapham has developed a potential treatment for asthma that blocks the entry of calcium into airway muscle cells. He has cofounded a company that will continue his work, including the development of drugs for use in asthma.
Daniel H. Conrad, Ph.D.
2011 Senior Award
Virginia Commonwealth University
Inhibiting Asthma by Blocking Messages from the Nervous System
The central nervous system (the brain and spinal cord) sends nerves out to the periphery, forming the peripheral nervous system. In the periphery, nerves can release chemicals that alter immunity. These chemicals are sensed by immune cells through proteins on their cell surface, which serve as ‘receptors’ for chemicals from nerves. One group of these receptors the “kainic acid receptors,” recognize the chemical glutamate. Dr. Conrad found that mice lacking these receptors have a notable reduction in the type of immunity associated with asthma. As a consequence these mice are resistant to asthma. Of special importance, a potential drug that blocks the function of kainic acid receptors also reduced asthma in mice. Dr. Conrad is working to further develop these drugs and, as well, to determine how kainic acid receptors promote asthma, looking for additional targets for therapy.
Marco Conti, M.D.
2001 Senior Award
Stanford University (Now at University of California, San Francisco)
Bringing New Precision (and Fewer Side Effects) to the Treatment of Asthma
For many years asthma was treated with theophylline, a drug that is related to caffeine. But the use of theophylline was limited by its side effects, some of which can be dangerous. Dr. Conti’s AAF-supported work has shown the feasibility of making drugs that are even more selective in their action, but just as effective, further reducing side effects, and some of these drugs have additional benefits, including suppression of inflammation. One of the drugs has been approved in Europe (as Daxas) and in US (as Daliresp) for the treatment of chronic lung disease with bronchitis. The use of these drugs in asthma is still in development
Michael Croft, Ph.D.
2000 Junior Award
La Jolla Institute for Allergy and Immunology
Stopping Inflammation in Asthma by Blocking Immune Cell Communication
In asthma, the immune system becomes overactive in the lungs, causing inflammation and damage to the lungs. Dr. Croft found a new way to block the overactive immunity in asthma by blocking proteins (called OX40 and OX40L) on the surface of immune cells. These two proteins interact with each other, allowing the immune cells to “talk” to each other, sending signals to activate immunity. Dr. Croft’s work defines a new target for the treatment of asthma.
Joseph L. DeRisi, Ph.D.
2001 Junior Award
University of California, San Francisco
A Simple Method for Detecting Known Viruses Affecting Asthma
Asthma attacks are often brought on by viral infection, but we understand too little about which viruses are especially prone to cause an attack. To solve this problem, Dr. DeRisi and his colleagues used cutting-edge technology to develop a tiny chip that can detect all known viruses that infect humans. This is being used to track viral infection in asthma. It has also been important in other illnesses and was used to first identify the SARS virus.
K. Christopher Garcia, Ph.D.
2005 Junior Award & 2011 Extension Award
New Information that Permits Designing Drugs for Asthma
Attacks of asthma are launched and sustained by molecules called ‘cytokines’, which circulate through the body to activate the immune system. 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, has defined the exact shapes of molecules on the cell surface that can bind to one of the cytokines that causes asthma. Because of the success of this work, he has received additional support from the AAF to design drugs that will block the binding by cytokines, arresting the immune responses that cause asthma. His work also led to an AAF Award to Gregory Verdine, at Harvard to use a different approach for drug development in asthma.
Eric Gouaux, Ph.D.
2008 Senior Award
Oregon Health & Science University
Revealing the Structure of a Protein on Muscle Cells Opens the Path to Drug Design in Asthma
In asthma, the muscles that surround the airways contract, closing the airways. The contracture of these muscles is controlled by proteins that reside on the surface of muscle cells and control the flow of ions (potassium, calcium) through the cell membrane. In his AAF-sponsored studies, Dr. Gouaux described for the first time the structure of one of these protein, called the ATP-gated P2X(4) ion channel. Knowledge of the structure of this protein greatly facilitates the design of drugs that might alter its activity and thus benefit asthma. Dr. Gouaux is using this information to screen for new drugs in the treatment of asthma.
Bruce D. Hammock, Ph.D.
2009 Senior Award
University of California, Davis
New Drugs for Lung Inflammation Directed at Lipids (fats)
Dr. Hammock's studies regard a family of lipid molecules called eicosanoids or oxylipins, the “oxy” indicating that the lipids have been oxidized. These molecules play an important role in inflammation – some strongly promote inflammation, while others inhibit inflammation. Dr. Hammock studied the effects of inhibiting one pathway in the formation of oxylipins and found that blocking this pathway reduced asthma in mice, especially when given when inhibitors of other pathways. In collaboration with investigators at Harvard, they are first testing an inhibitor of oxylipin formation in severe lung inflammation, and they are working on approval to use a second drug. Both drugs may find use in asthma. Dr. Hammock also developed tests to determine what oxylipins are found in the lungs of patients with asthma, and he has made these tests available for studies of asthma by other investigators. This opens the way to identifying different types of asthma and to monitoring the effects of therapy
William Harnett, Ph.D.
2009 Senior Award
University of Strathclyde, UK
Finding Proteins in Worms to Treat Asthma
Prior studies have suggested that infection with certain parasitic worms may protect against asthma. Dr. Harnett has been studying molecules from parasitic worms in order to understand the mechanisms of this effect. From one worm, he isolated a protein that can inhibit inflammation, and he has now identified much smaller molecules that mimic the effects of the worm component in inhibiting inflammatory cells in vitro. This opens a pathway that might allow the use of such small molecules in therapy, instead of testing the use of worms.
V. Michael Holers, M.D.
2006 Senior Award
University of Colorado, Denver
Taming Natural Defenses that Cause Harm in Asthma
Dr. Holers has shown that natural defenses, normally used against infections, may cause harm in asthma. These defenses are collectively called the complement system. Dr. Holers has shown in animals that blocking one part of this defense system prevents inflammation in asthma.
Sven-Eric Jordt, Ph.D.
2007 Early Excellence Award & 2010 Extension Award
Control of Asthma by Nerves in the Lung
It has long been known that stimulation of nerves in the lung can open and close the airways, but Dr. Jordt finds that nerves also control inflammation in the lung. In particular, there is an important role in the lung for nerves that were once thought only to send signals directly to the brain (such as pain signals). It is now clear that these nerves do more than that. In particular, when these nerves are stimulated in a specific manner, they release chemicals into the lung that promote inflammation and asthma. In animal models for asthma, Dr. Jordt has tested drugs that block this role of nerves in inflammation. This new approach strongly inhibits asthma in animals. Because of the success of this work, Dr. Jordt was given additional AAF funding to pursue this new avenue of therapy.
Christopher L. Karp, M.D.
2006 Senior Award
Cincinnati Children's Hospital Medical Center (Now at Gates Foundation)
How Insects in House Dust Activate Asthma
Asthma is strongly associated with exposure to dust mites, tiny insects that live in bedding, carpeting, and cloth furniture. It has been known for some time that people with asthma often have dust mite allergies, and this contributes to asthma. Allergies result from a harmful immune response against otherwise innocuous proteins (allergens). For most allergens, it is unclear why they generate this harmful response, but Dr. Karp has shown why this is so in the case of dust mites. The immune system has special sensors that signal the presence of microbes (such as bacteria), activating the immune system to respond to infectious threats. Dr. Karp showed that a protein released by mites, called Der p 2, activates the immune sensor for bacteria, setting off potent immune responses to dust mites. He has since shown that mites produce a whole series of related proteins that have the same effect. Thus mites make not only make allergens but also signal the immune system to make an intense response to these allergens, setting off asthma.
Robert Lefkowitz, M.D.
2000 Senior Award & 2012 Nobel Laureate in Chemistry
“Arresting” Inflammation in Asthma
The cells that cause inflammation in asthma express proteins called β-arrestins. Dr. Lefkowitz has previously shown that heart and vascular diseases involve β-arrestins. As part of his AAF Award, he and his colleague, Julia Walker, demonstrated in animals that β-arrestins are required for the development of asthma. This led to a patent regarding inhibition of β-arrestins in asthma, and Dr. Walker is pursing studies of how arrestins might be blocked to prevent asthma. β-arrestins alter the function of receptors on cells called “G Protein Coupled Receptors.” In 2012, Dr. Lefkowitz won the Nobel Prize for his work in this area.
Xiaoxia Li, Ph.D.
2009 Senior Award
The Cleveland Clinic
A Link Between Cells that Line the Airways and the Initiation of the Immune Response that Causes Asthma
Asthma involves a specific type of immunity, called Th2 immunity. Dr. Li has identified an important step in the development of Th2 immunity that involves a protein called Act1. Although Act 1 is found in immune cells, Dr. Li found that it is also expressed in airway epithelial cells, the cells that line the airways. Moreover, the expression of Act1 in epithelial cells plays an important role in regulating immunity in the lungs. Based on these insights, she is developing new drugs to test in asthma.
Roderick MacKinnon, M.D.
2007 Senior Award, 2013 Extesion Award & 2003 Nobel Laureate in Chemistry
The Structure of a “Channel” on Airway Muscle Cells Opens the Path to New Therapies
In an attack of asthma, the muscles around the airways tighten, narrowing the airways and reducing the flow of air. Control of the airway muscles, therefore, is a major part of asthma therapy. The contraction of these muscles is controlled by the flow of potassium in and out of the cell through tunnels in the cell wall called “channels.” One type of channel, the BK channel, is particularly important in asthma. Dr. MacKinnon has, for the first time, determined the structure of most of the BK channel (the portion that lies inside the cell). The structure reveals how the channel is opened or closed depending on the level of calcium inside the cell. Dr. MacKinnon is using information from these studies to screen for drugs that alter the BK channel in a manner that will reverse he airway narrowing in asthma.
Andrew N. McKenzie, Ph.D.
2010 Senior Award
Medical Research Council, UK
A New Type of Cell is Linked to Asthma
Dr. McKenzie discovered a new type of cell that plays a major role in asthma. He called these cells nuocytes. With his AAF Award, he showed how the development and function of nuocytes is regulated. These studies have identified new potential targets for treating asthma by blocking the role of nuocytes
John S. McMurray, Ph.D.
2011 Senior Award, 2014 Extension Award
University of Texas M.D. Anderson Cancer Center
Shifting Immunity Away from the Type of Immunity That Causes Asthma
Asthma is associated with a distinct type of immunity called a “Th2” immunity. This response is dependent on a protein in immune cells called Stat6. Dr. McMurray is studying Stat6, looking for ways to block its effects. He has designed a series of potential drugs that can enter immune cells and block the activity of Stat6. The results have been impressive. One of the drugs can block asthma in mice when it is administered into the airways. Importantly, it can reverse established changes in the mouse asthma model. For example, it reverses the asthma-related expansion of the number and size of cells that produce mucus and it reverses difficulty in breathing. In 2014, Dr. McMurray was granted a fourth year of support (an Extension Award) to continue the development of this potential drug.
Victor Nizet, M.D.
2008 Senior Award
University of California, San Diego
A New Target for the Treatment of Asthma
Asthma is marked by chronic inflammation in and around the airways. Dr. Nizet is studying a molecule inside inflammatory cells called hypoxia-inducible transcription factor-1α (HIF1α), so named because it was first discovered as a protein that increases in cells when they lack oxygen. HIF1α proves to be an important molecule in the regulation of inflammation. Dr. Nizet has shown that mice deficient in this molecule are highly resistant to asthma, and he has been able to block asthma in mice by giving them an inhibitor of HIF1α, opening the way to new methods for the treatment and/or prevention of asthma.
Eric N. Olson, Ph.D.
2006 Senior Award
University of Texas Southwestern Medical Center
Controlling Genes that Control Asthma
The closing of airways in asthma involves inappropriate contraction of airway muscles, which also grow in size and strength. These changes are genetically regulated, and Dr. Olson has identified molecular pathways in the cell that control the genetic changes. These studies have the potential to lead to the development new therapies, including drugs that could mimic the actions of corticosteroids with fewer side effects.
Jonathan D. Powell, M.D., Ph.D.
2011 Senior Award
Johns Hopkins University
Teasing Out Molecular Pathways That Promote Asthma
In his studies of asthma, Dr. Powell studied immune cells for a series of enzymatic reactions that together form the “mTOR” signaling pathway. When this pathway is activated it causes several molecules in immune cells to aggregate in a manner that promotes an asthma-related immune response. Dr. Powell found that this process works by activating an enzyme called SGK1. Mice without SKG1 were shown to be resistant to asthma in two different mouse models. Further, a potential drug that blocks the activity of SGK1 reduces asthma-related immunity and inflammation. Dr. Powell’s studies have thus identified a new potential target for the treatment of asthma, and he is pursuing this possibility.
Daphne Preuss, Ph.D.
2004 Senior Award
University of Chicago (Now at Chromatin, Inc.)
The Role of Pollens: More Than We Thought
Pollens are a major trigger to allergy and asthma. Testing for allergy to pollens involves skin tests with extracts from the plants that produce pollens. Dr. Preuss and her colleagues have shown that the preparation of these extracts often removes the parts of allergens that are most important in causing allergy and asthma. She developed new tests that can rapidly, accurately, and inexpensively detect allergies using only a small amount of blood. This holds great potential for defining allergies in asthma and for customizing therapy to each individual.
2003 Senior Award
Treatment of Asthma with a Drug Previously Used Only on the Skin
Dr. Radzioch’s studies led her to test a compound called S28463, a.k.a. resiquimod, developed by 3M Pharmaceuticals. This drug is clinically used as a topical treatment for skin conditions, including skin cancer. When Dr. Radzioch gave resiquimod to animals, it almost completely blocked the development of asthma. 3M has licensed resiquimod to Graceway Pharmaceuticals, but it has not yet been tested in humans with asthma.
Kodi S. Ravichandran, Ph.D.
2008 Senior Award & 2011 Extension Award
University of Virginia, Charlottesville
Proper Burial for Dying Cells in the Lung Prevents Asthma
There is a constant turnover of cells in most tissues in the body, and this is true also for cells that line the airways. The cells that die as part of the turnover have to be cleared without harm to the rest of the tissue. Uncleared dying cells can set off inflammation, and inflammation in the lungs can lead to asthma, so this inflammation must be controlled. In his AAF-sponsored studies, Dr. Ravichandran demonstrated that when airway cells die, they can be removed by neighboring airway cells, and this cell clearance process causes the healthy airway cells to suppress inflammation. His studies indicate that they do this in part by producing a molecule (a "cytokine") called IL-10. Further, treating mice with IL-10 breathed into airways reduces asthma. This discovery opens a new chapter in our understanding of how lung inflammation is controlled.
Joshua Rokach, Ph.D.
2012 Senior Award
Florida Institute of Technology
Testing a New Drug in the Treatment of Asthma
The lung inflammation of asthma is usually marked by an abundance of a particular white blood cell, the eosinophil. Eosinophils are attracted to the lung by the local release of a chemical called 5-Oxo-ETE. In his AAF studies, Dr. Rokach has developed a drug to block this effect of 5-Oxo-ETE. Using an animal model in which eosinophils accumulate in the skin of macaques, he has shown the effectiveness of this drug in blocking the accumulation of eosinophils. He is now testing the effects of this drug in a macaque model of asthma.
Bert L. Semler, Ph.D.
2008 Senior Award
University of California, Irvine
A New Target for Treating Viral Infection -- Common Viruses Hijack a Host Enzyme to Begin Replication
Viral infections of the lung can set off asthma, and severe viral infections in children are associated with recurrence of asthma for years. The most common type of virus that sets off an attack of asthma is rhinovirus, the cause of the common cold. This is part of a larger family of viruses called picornaviruses. Dr. Semler sought to find a target for treating all picornavirus infections. As part of his AAF studies, he identified an enzyme in human cells called TDP2, which allows picornaviruses to replicate by removing a small protein at one end of the viral genetic material. This provides a new target for the treatment of viral infections. TDP2 is also involved in repairing DNA in cells, so the trick will be to block its role in permitting viral infection without long-term effects on its normal functions. Regardless, this finding provides the possibility of treating viral infections that were previously untreatable.
Kevan M. Shokat, Ph.D.
2003 Senior Award
University of California, San Francisco
Clinical Trials in Asthma for a New Drug that Blocks Inflammation
Dr. Shokat studied an enzyme called PI 3-kinase, which plays a major role in the initiation of inflammation. He developed a new drug to block PI 3-kinase, and he licensed this to a start-up company, Intellikine, which has since partnered with Infinity Pharmaceuticals to test this drug in patients with asthma. If successful, this will provide an entirely new approach to the treatment of asthma.
Satish K. Srivastava, Ph.D.
2008 Senior Award & 2013 Extension Award
University of Texas Medical Branch, Galveston
Turning an Old Diabetes Drug to New Use in Asthma
In studies of mice, Dr. Srivastava has found that a drug once tried without success in the therapy of diabetic neuropathy does much better in treating asthma. The drug belongs to a family of agents called aldose reductase inhibitors. Dr. Srivastava has found that these drugs not only reduce inflammation, but also reduce the type of immunity that is associated with asthma. They also effectively reduce asthma in mice when given either by mouth or inhaled into the nose. Because these drugs were previously evaluated in large trials of humans with diabetes and found to be relatively safe, they should be readily available for clinical trials in patients with asthma. Indeed, Dr. Srivastava’s group is currently planning for human trials with one of these drugs, fidarestat.
Jonathan S. Stamler, M.D.
2003 Senior Award
Duke University (Now at Case Western Reserve University)
Restoring the Ability to Keep Airways Open in Asthma
Cells in normal airways make a small molecule called GSNO, which keeps the airways open. Dr. Stamler and his colleagues found that GSNO falls to low levels in asthma, and that asthma in animals is improved when GSNO is restored. He also developed drugs that block the enzymatic breakdown of GSNO. Based on this work, N30 Pharmaceuticals has initiated clinical trials of GSNO in patients with asthma.
Mary E. Sunday, M.D., Ph.D.
2007 Senior Award
Blocking a Protein in the Airways that Promotes Asthma Pathology and Pathology Research
Asthma involves inflammation of the lung airways. By studying asthmatic responses to allergens and air pollutants in mice, Dr. Sunday has found that airway inflammation is promoted by a protein made locally in the airways, called ‘gastrin-releasing peptide’ (GRP). By blocking GRP, Dr. Sunday markedly reduced both airway inflammation and airway tightening in mice with asthma. The effect of GRP blockade was substantially greater than that observed with steroid treatment in the same mouse models. Because of these beneficial effects of GRP blockade in mice, this new treatment is being considered for testing in humans with asthma.
Jenny P-Y Ting, Ph.D.
2005 Senior Award
University of North Carolina at Chapel Hill
Newly Discovered Pathways to Inflammation
Several years ago, Dr. Ting described a group of related proteins that are used throughout the animal and plant kingdoms to control immunity and inflammation. She called these CATERPILLER proteins, recently named NLR proteins. Her studies have led to the discovery of how these proteins work in asthma and in a wide variety of immunologic disorders. One of her key objectives is to define the role of NLR proteins in lung injury, inflammation, and infection, and especially how these proteins affect the outcome of asthma.
Yaping Tu, Ph.D.
2011 Early Excellence Award
Creighton University School of Medicine
A New Approach to Opening the Airways in Asthma
Airway smooth muscle cells, like all cells, respond to their environment through proteins on the cell surface. These proteins sense and respond to molecules outside the cell, so they are called cell-surface “receptors.” Dr. Tu studied one group of such receptors, called G protein coupled receptors (GPCRs), looking in particular at other molecules in airway smooth muscle cells that regulate the function of these receptors. In doing so, he found one regulatory molecule (RGS2) that reduces tightening of airway muscles, a hallmark of asthma. Further, he found that airway muscle from patients with asthma had reduced levels of this regulatory molecule, suggesting that airway narrowing in asthma might be a consequence of reduced RGS2. If this were so, treatments to increase RGS2 would be a new approach for the treatment of asthma. Based on his AAF work, Dr. Tu has received NIH support to continue this work both in his own laboratory and in collaborative studies with others at his University.
Ralph Weissleder, M.D., Ph.D.
2006 Senior Award
Massachusetts General Hospital
Visualizing the Lungs During an Attack of Asthma
To better understand what causes asthma, it would be useful for scientists to see exactly what happens during asthma: how the airways close and open, what changes occur in the cells and fluids in airways, and what changes occur in the cells and enzymes that surround the airways. Dr. Weissleder is a leader in exploring new approaches to look at living tissue and, with his Award from the AAF, he has turned his attention to the asthmatic lung, bringing new understanding to the changes that occur in asthma. Dr. Weissleder has begun with studies of rodents, but his work will also have future application to humans with asthma.
H. Eric Xu, Ph.D.
2010 Senior Award
Van Andel Research Institute
Changing the Structure of Steroids to Retain Their Anti-Inflammatory Benefits But Not Their Side Effects
Specific types of steroids (glucocorticoids) markedly reduce inflammation, and they are an important part of therapy for asthma.. They have significant side effects, including diabetes, obesity, thin bones, and cataracts, but these are greatly reduced by use of inhaled steroids, rather than systemic steroids (pills or injections). It would nonetheless be useful both in asthma and in other diseases if glucocorticoids could be developed that retained their anti-inflammatory effect but lost their side effects. Dr. Xu has preliminary evidence that this may be possible, including the identification of several altered forms of cortisol in which there is at lease partial separation of benefit from side effects. Although these studies are still at an early stage, they are significant because they open the path to a very important advance in the treatment of inflammation.