Our Services

SCCOR Grant

Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh Specialized Center of Clinically Oriented Research in Pediatric and Adult Pulmonology

Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh Specialized Center of Clinically Oriented Research (SCCOR) in Pediatric and Adult Pulmonology was established in 2006 with a $12.8 million, five-year grant from the National Heart, Lung and Blood Institute of the National Institutes of Health.

Host Factors in Fungal Allergy and Fibrosis

The four SCCOR projects supported by the grant seek to define the molecular pathways that regulate adaptive immunity to antigens and to improve the understanding of interactions between immune cells and parenchymal cells in the development of fibrosis or allergic responses. In the long term, this knowledge will be used to improve diagnosis and treatment of patients with chronic lung diseases, particularly allergic and fibrotic lung diseases.

One focus of the center’s research is to investigate the immune response to Aspergillus fumigatus, a common fungus. The goals of this work include understanding why some cystic fibrosis and allergy patients exposed to the fungus develop allergic bronchopulmonary aspergillosis (ABPA) while most patients do not, and identifying key molecules involved in inducing an immune response to Aspergillus that could become targets for developing therapies to prevent the disease. Another focus of the research is to understand the molecular mechanisms underlying idiopathic pulmonary fibrosis to improve diagnosis and treatment of this serious lung disease that affects more than 100,000 nationwide.

Projects and Project Leaders:

Administrative Core
Principal Investigator, Jay K. Kolls, MD
E-mail: jay.kolls@chp.edu

Project I: Immune Tolerance and Inflammation in ABPA in patients with Cystic Fibrosis

Principal Investigator, Jay K. Kolls, MD
E-mail: jay.kolls@chp.edu
Graduate Program Affiliation: University of Pittsburgh School of Medicine, Graduate Program in Immunology
Divisional Web site: Children’s Hospital of Pittsburgh of UPMC, Division of Pediatric Pulmonary Medicine, Allergy and Immunology

Allergic bronchopulmonary aspergillosis (ABPA) is an inflammatory lung reaction to a fungus, Aspergillus fumigatus, that occurs in some cystic fibrosis patients and asthma patients. It causes cough, wheezing, decreased lung function and, in some cases, chronic lung damage. This project investigates how and why Aspergillus causes these symptoms in some cystic fibrosis and asthma patients, but not in the majority of patients exposed to the fungus.

The answers to such questions will provide a better understanding of the underlying mechanisms of the disease, contribute to efforts to improve treatment and offer new information that could be helpful in developing ways to prevent allergies.

Everyone inhales Aspergillus molds, but most people do not develop allergies to them. ABPA occurs in 4-15 percent of cystic fibrosis patients and in 1 percent or fewer asthma patients. Project investigators hope to define the currently unknown mechanisms involved in the immune response to Aspergillus fumigatus. They believe that how a patient responds likely depends on both innate and adaptive immunity. And they have defined key molecules involved in the earliest immune responses to Aspergillus that may be significant in determining whether a patient will remain tolerant to the fungus or have an allergic, inflammatory response. The project includes testing several hypotheses about immune tolerance and inflammation related to ABPA and designing a trial to identify genetic risk factors involved in the disease.

More specifically, the approach involves:

  • Testing the hypothesis that cystic fibrosis patients with ABPA require Dectin-1 ( a receptor that recognizes fungal carbohydrate, b1,3-glucan) expression on peripheral blood monocytes/dendritic cells and that the binding of Aspergillus fumigatus to Dectin-1 produces a greater inflammatory response in patients with ABPA than in patients who do not have the disease.
  • Testing the hypothesis that T-cells from cystic fibrosis patients with ABPA have a decreased adaptive T-regulatory function critical to the development of tolerance.
  • Testing the hypothesis that specific antifungals may block mechanisms that promote inflammation in cystic fibrosis patients with ABPA.

The project is led by principal investigator Jay K. Kolls, MD, chief of the Division of Pulmonary Medicine, Allergy and Immunology at Children’s Hospital of Pittsburgh of UPMC and director of the Asthma Center and Laboratory of Lung Immunology and Host Defense. Co-investigators include Anuradha Ray, PhD, professor of medicine and immunology, University of Pittsburgh School of Medicine; Chad Steele, PhD, associate professor of medicine at the University of Alabama School of Medicine; Daniel Weiner, MD, medical director of the Pulmonary Function Laboratory at Children’s Hospital and assistant professor of pediatrics; Yatin Vyas, MD, assistant professor of pediatrics and immunology; and Todd Green, MD, and Jonathan Spahr, M.D., both assistant professors of pediatrics.


Project II: Host Factors Regulating Allergic Responses to Aspergillus

Principal Investigator, Anuradha Ray, PhD
E-mail: raya@pitt.edu
Graduate Program Affiliation: University of Pittsburgh School of Medicine, Graduate Program in Immunology
Divisional Web site: University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine

Aspergillus fumigatus is a fungus that can cause allergic bronchopulmonary aspergillosis (ABPA), an inflammatory lung reaction that occurs in 4-15 percent of cystic fibrosis patients and in 1 percent or fewer asthma patients. ABPA causes cough, wheezing, decreased lung function and, in some cases, chronic lung damage. This project investigates aspects of how a patient’s immune system responds to Aspergillus, focusing on the role of certain molecules that previous studies suggest influence the immune response.

Through their research, project investigators hope to identify key molecules involved in inducing an immune response to Aspergillus that could become targets for developing therapies to prevent ABPA.

Alveolar macrophages, neutrophils and dendritic cells promote both inflammatory and protective responses against invading lung pathogens, such as Aspergillus. Previous studies have led project researchers to hypothesize that molecules important in the defense against Aspergillus include Dectin-1 and surfactant proteins that are highly expressed in the lung. The underlying mechanisms involved in the process are not well understood. In this project, animal models deficient in Dectin-1 are studied to determine whether the immune response to Aspergillus is changed because of those deficiencies. In addition, other animal models that over express surfactant proteins are studied to determine whether the over expression of the surfactants protects them from experiencing an allergic response to Aspergillus.

More specifically, the project involves:

  • Defining the effect of Aspergillus on the adaptive immune response and its dependence on the interactions between the fungus and host cell surface components beta glucan-Dectin-1 and TLR2. These molecules important in recognizing Aspergillus are believed to play a key role in the immune response to the fungus.
  • Determining the effect of certain surfactant proteins on Aspergillus-induced immune responses. This aspect of the project involves investigating whether the over expression of surfactant proteins SP-A and SP-D in animal models protects against Aspergillus.
  • Determining whether certain antigens that are present in Aspergillus can be used as a vaccination to prevent an allergic response. Prior to being infected with Aspergillus, animals are immunized with antigens, such as Aspf1, that play an immunodominant role. Researchers are investigating whether repeated exposure to immunodominant antigens can induce tolerance of the entire pathogen.

The project is led by principal investigator Anuradha Ray, PhD, professor of medicine and immunology at the University of Pittsburgh School of Medicine. Co-investigators include Chad Steele, PhD, associate professor of medicine at the University of Alabama School of Medicine, and Timothy Oriss, PhD, research assistant professor, University of Pittsburgh Division of Pulmonary, Allergy and Critical Care Medicine.


Project III: Surrogate Biomarkers for Disease Progression in IPF

Principal Investigator, Naftali Kaminski, MD
E-mail: kaminskin@upmc.edu

The Dorothy P. & Richard P. Simmons Center for Interstitial Lung Diseases

Graduate Program Affiliation: Cellular and Molecular Pathology Graduate Training Program
Divisional Web site: University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine

This project is focused on developing ways to improve the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF), a disease characterized by progressive scarring of the lung that affects more than 100,000 patients in the United States. Currently available medical therapies have been ineffective in treating IPF, with the exception of lung transplantation. Moreover, current methods of diagnosis, including high resolution imaging and pulmonary function testing, report damage already done to the lung, but fail to provide information important to understanding the future course of a patient’s disease or the molecular events that led to it.

Focusing on the peripheral blood mononuclear cells (PBMC) and plasma of IPF patients, project investigators hope to identify and evaluate a set of molecular signatures, or biomarkers, that will provide insight into the severity of a patient’s disease and its progression. Recent studies suggest that gene expression patterns in those blood cells and in proteins carried in the blood stream may contain disease-related signatures that reflect a patient’s defense response to the disease process. Project investigators suspect that a patient’s defense mechanisms may determine the rate of IPF progression based on evidence such as observations that progression of IPF varies widely among patients, and that treatment with an immune-boosting cytokine can have a positive effect on survival, even though it does not improve lung function.

Surrogate biomarkers in peripheral blood that offer critical information about a patient’s disease have several potential benefits as a tool for predicting the course of IPF in patients and better informing and tailoring their treatment, as well as for developing new drug therapies and moving them from the bench to the bedside more quickly.

The approach toward achieving the goal of identifying these informative biomarkers includes several components. Specifically, the project aims to:

  • Create from the UPMC Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease database and short-term IPF outcome data a cohort of IPF patients who will be routinely evaluated to study the relationship between biomarkers and disease progression.
  • Analyze protein expression levels in the serum of target molecules using a multianalyte bead-based protein profiling assay.
  • Identify a gene expression signature in PBMC that is diagnostic and provides information related to the progression of the disease and the effects of treatment.
  • Determine the role that adaptive immunity plays in the progression of IPF.

The project is led by principal investigator Naftali Kaminski, MD, associate professor of medicine at the University of Pittsburgh School of Medicine and director of the UPMC Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease. Co-investigators include Kevin F. Gibson, MD, associate professor of medicine and member of the Simmons Center staff, Steven R. Duncan, MD, an associate professor of medicine at the university, and Ivan Rosas, MD, associate professor of medicine and member of the Simmons Center staff.


Project IV: KGF and Inhibition of Pulmonary Fibrosis

Principal Investigator, Prabir Ray, PhD
E-mail: rayp@pitt.edu

The Dorothy P. & Richard P. Simmons Center for Interstitial Lung Diseases

Graduate Program Affiliation: University of Pittsburgh School of Medicine, Graduate Program in Immunology
Divisional Web site: University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease characterized by progressive scarring of the lung that leads to respiratory failure. No current therapies, with the exception of lung transplantation, have been effective in treating this disease that affects an estimated 100,000 patients in the United States.

This project investigates the molecular mechanisms involved in the disease and explores the role of growth factors that studies suggest work to prevent the development of pulmonary fibrosis, the excessive growth of fibrous tissue reduces the ability of the lung to function properly. With a better understanding of these mechanisms, project researchers hope to be able to identify the best combinations of growth factors for inhibiting fibrosis and promoting lung repair that can be used in developing effective therapies for IPF.

IPF involves the destruction of normal epithelial cell structure, proliferation of fibroblasts, the depositing of connective-tissue matrix proteins and inflammation. Project researchers, in earlier studies, have found evidence that increased expression of a small molecule, keratinocyte growth factor (KGF), works to protect the lung from fibrosis. Although the underlying mechanism for this protection is not known, studies suggest several possibilities. Using mouse models, researchers are exploring those possibilities to more fully understand the protective process with an overall goal of determining how to guard epithelial cells from injury and inhibit fibrosis.

More specifically, their approach toward achieving that goal includes:

  • Investigating the hypothesis that certain factors induced by KGF in epithelial cells inhibit the development of pulmonary fibrosis. This aim involves characterizing the role of the chemokines CXCL9, CXCL10 and CXCL11 and of STAT1 in the KGF-mediated process that works to protect the lung from fibrosis.
  • Defining the role that Wnt/b-catenin signaling has in the KGF-mediated process of protecting the lung from fibrosis. The Wnt molecule regulates b-catenin and when b-catenin is down-regulated, epithelial cells undergo fibrosis. This investigation focuses on understanding that process and learning whether growth factors such as KGF are able to prevent b-catenin down-regulation.
  • Defining the role that the inhibitor of differentiation-1 (Id1) molecule has in the KGF-mediated process of protecting the lung from fibrosis. This involves investigating the hypothesis that KGF inhibits transforming growth factor-b-induced signaling mechanisms and the production of TGF-b in epithelial cells and that this process may prevent epithelial cells from differentiating into fibroblasts.

The project is led by principal investigator Prabir Ray, PhD, associate professor of medicine and immunology at the University of Pittsburgh School of Medicine. Danielle Morse, MD, assistant professor of medicine, is the project co-investigator.


Clinical / Biostatistics Core

Principal Investigator, Joseph M. Pilewski, MD
E-mail: pilewskijm@upmc.edu

Divisional Web site: University of Pittsburgh, Division of Pulmonary, Allergy and Critical Care Medicine

Co-Principal Investigator, Howard Rockette, PhD
E-mail: herbst@pitt.edu

Biographical Information: Howard Rockette, PhD

 

UPMC University of Pittsburgh Medical Center University of Pittsburgh logo Children's Hospital of Pittsburgh of UPMC logo
Last Update
September 25, 2014
  • Increase/Decrease Text Size
  • Print This Page
Last Update
September 25, 2014
top