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For Immediate Release
Researchers Receive $12.8 Million NIH Grant to Improve Diagnosis/Treatment of Chronic Lung Disease
Pittsburgh, Pa. - October 2, 2006 -
Children's Hospital of Pittsburgh of UPMC and University of Pittsburgh School of Medicine researchers have been awarded a $12.8 million grant to improve the diagnosis and predict the therapeutic response of several devastating lung diseases.
This five-year grant from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) establishes Children's and the University of Pittsburgh as a Specialized Center of Clinically Oriented Research (SCCOR) in Pediatric and Adult Pulmonology. This kind of center award is designed to facilitate more rapid translation of basic research findings into effective therapies for specific and troublesome diseases. Jay K. Kolls, MD, principle investigator and a professor of Pediatrics and Immunology at Pitt, and his collaborators not only hope to determine prevention strategies for patients suffering from allergic and fibrotic lung diseases, but also anticipate developing more effective treatments for these patients. The SCCOR consists of four research projects and two cores.
One project is to understand why and how Aspergillus (group of molds that are ubiquitous in our environment) causes lung damage in patients with suppressed immune systems. This is particularly important for the health of children because this mold can cause significant lung damage in cystic fibrosis and asthma patients.
Allergic bronchopulmonary aspergillosis (ABPA) is an intense inflammatory reaction to the fungus, Aspergillus fumigatus, and can cause irreversible lung damage in patients with cystic fibrosis (CF) and asthma. Aspergillus, the mold which elicits this immune response, is very common in the environment and found worldwide. Although Aspergillus is not a health problem for most people, it can lead to pneumonia in patients with severely suppressed immune system and cause allergic damage to the airways of patients with CF or asthma. However, scientists do not understand why some patients develop airway damage and others do not.
"Everyone inhales Aspergillus molds. What we need to determine is why and how some develop an allergy to it, and others do not," said Kolls, who is the chief of Pulmonary Medicine, Allergy, and Immunology at Children's. "We don't know why some patients develop this disease and others do not. Ideally we want to be able to predict who is susceptible to the disease and provide better treatments for patients."
Co-investigator Chad Steele, PhD, co-director of the Laboratory of Lung Immunology and Host Defense at Children's and an assistant professor at Pitt, has defined key molecules that initiate the earliest immune responses to Aspergillus. These molecules may be significant in determining which patients develop a protective immune response while others develop an immune response which damages the lung.
This allergic response is developed mostly by CF patients, Kolls said. CF is progressive and attacks the lungs.
The disease affects more than 30,000 children and adults in the United States. Currently, the life expectancy of a child born with cystic fibrosis is 32 years. Pennsylvania is one of only 11 states that screens for lung disease.
The Antonio J. and Janet Palumbo CF Center at Children's, follows more than 430 patients suffering from the life-shortening and incurable disease. Upon review, more than one-third, or 180, of those patients have Aspergillus in their lungs.
Kolls explains that research by co-investigator and project leader Anuradha Ray, PhD, of the Division of Pulmonary, Allergy and Critical Care Medicine (PACCM) at Pitt, has shown that regulatory T cells, also known as the "the gatekeepers," can suppress allergic responses and control allergies in humans. The ability of these cells to control allergic responses may be critical in determining which patients develop allergy and which patients do not develop lung damage. Dr. Ray's project will investigate interactions between innate and adaptive immune mechanisms regulating ABPA. Co-investigators on this project include Chad Steele, PhD of CHP,and Timothy Oriss, PhD, of PACCM at Pitt.
"Our ultimate goal is to learn if mobilization of these suppressor cells can help control the allergy thereby creating more of an immune response in these patients," Kolls said. " By more clearly defining how this disorder develops through our basic research we will be in a position to develop more effective and specific treatment and prevention strategies and, in this way, provide a better quality of life for these patients."
"Understanding how microbes interact with host immune cells to cause lung disease is absolutely critical and Jay Kolls is one of the world's leaders in this area. This award has permitted him to assemble an outstanding team and will facilitate new discoveries that have the potential to benefit children and their families everywhere," said David Perlmutter, MD, Children's physician-in-chief and scientific director.
The other disease that the SCCOR will focus on is to improve treatment and diagnosis of patients with Idiopathic Pulmonary Fibrosis (IPF). Idiopathic Pulmonary Fibrosis is a disease characterized by progressive scarring of the lung without any recognizable reason. The disease affects more than 100,000 patients in the US and currently there is no proven therapy except lung transplantation. Furthermore, there is no good way to diagnose the disease before significant lung damage has occurred or to predict the outcome of the disease.
Co-Investigators from the Dorothy P. and Richard P. Simmons Center For Interstitial Lung disease and the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh will attempt to design better methods for diagnosis and treatment of IPF. Naftali Kaminski, MD, associate professor of Medicine, Pathology and Human Genetics and director of the Simmons Center, is leading a project with Kevin Gibson MD that will follow up patients to identify changes in their genes that predict disease progression. These changes may help to understand what causes the disease and to design better drugs.
"The numbers tell us that only 50% of patients survive 3 years. In reality, some of them survive much longer, while others do very badly, we currently have no way to tell" said Dr Gibson, Associate Professor of Medicine "this study should allow us to predict how the patient will do and to try and guide their options".
Steven R. Duncan, MD, associate professor of Medicine, and a co-investigator with Dr. Kaminski has discovered that many patients with IPF have exaggerated immune response. This new observation may suggest that not all patients will respond to the same therapy and may suggest that some patients will respond to specific drugs that modify the immune system.
"It is now accepted that you can get lung fibrosis by many mechanisms, but we still try to treat all patients the same way (and we fail)" said Dr Kaminski, who is also the director of the Lung Translational Genomics Center that aims to use the Human Genome information to understand lung disease "This project should allow us what genes are active in a specific patient during disease progression and in the future tailor a therapy."
Prabir Ray, PhD, Associate Professor of Medicine in the Division of Pulmonary, Allergy and Critical Care Medicine at the University of Pittsburgh leads the fourth project on the SCCOR and has shown that certain growth factors can protect the lung against the development of fibrosis in mice. He will further study the mechanisms of these protective effects and will examine whether specific therapies could be developed. Co-investigators on Dr. Ray's project include Danielle Morse, MD, of PACCM and Satdarshan Pal Singh Monga, MD, of the Department of Pathology at Pitt.
Dr Kaminski said that Dr Ray's experiments are critical because they may help develop approaches not only to halt fibrosis but maybe even to reverse it.
The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease was established 5 years ago through a generous donation of the Simmons family. More than a 1000 patients with Interstitial Lung Disease are being followed up in the center; around 350 are patients with Idiopathic Pulmonary Fibrosis. In addition to access to multiple research protocols, the Center provides personal care by physicians who are experts in Interstitial Lung Diseases, information and education programs and an active support group.
The grant also involves as core leaders Joseph Pilewski, MD, who is co-director of the Adult Cystic Fibrosis Program at the Antonio J. and Janet Palumbo Cystic Fibrosis Center of Children's Hospital of Pittsburgh, and Medical Director of the Lung Transplant Program at the Division of Pulmonary, Allergy and Critical Care Medicine of the University of Pittsburgh Medical Center, and Howard Rockette, PhD, who is professor and chair of the department of Biostatistics at the University of Pittsburgh Graduate School of Public Health.
June 11, 2008
June 11, 2008