Core Research Programs
PCPB Faculty Members are engaged in a wide variety of research projects. The list below highlights our main areas of “wet bench research”.
Center for Translational Lung Biology
The Center for Translational Lung Biology was designed to enhance lung and critical illness research by successfully integrating the clinical, translational, and basic science expertise in lung biology and critical illness, through its ability to provide the proper resources, organization, core facilities, and by supporting key recruitments. The Center is led by Dr. Jason Christie. The CTLB will work with the PCBC to provide key resources to SOM/University-wide researchers and trainees to vertically integrate basic and clinical science research through non-overlapping translational core functions focused on advanced lung diseases, lung transplantation, and critical illness syndromes. This will include a: 1) Biosample Acquisition and Clinical Data Management Core, 2) a Molecular Biology and Measurement Core, 3) a Lung Disease Modeling Core, 4) a vibrant seminar series including extramural speakers, partnered with other centers, and 5) outreach, with a focus on interacting closely with existing Departments, Centers, and Institutes to support lung disease research, especially in immunology (IFI), environmental lung diseases (CEET), epidemiology (CCEB), pediatric and neonatal lung disease (CHOP), Orphan Diseases, pulmonary vascular disease (CVI), lung transplantation (Dept. of Surgery), experimental therapies (ITMAT), and lung cancer (ACC).
Asthma/Rare Lung Disease Research
This is an interdisciplinary group with a focus on asthma, lymphangioleiomyomatosis and other airways and orphan diseases. The group is led by Dr. Vera Krymskaya. Other members include Drs. Andrea Apter and Elena Atochina-Vasserman. Research from this group is supported by RO1 funding and Foundation support.
Vera P. Krymskaya, PhD, MBA, Fellow, College of Physicians of Philadelphia, has been leading a Laboratory of Rare Lung Diseases focusing on signaling mechanisms underlying sporadic pulmonary lymphangioleiomyomatosis (LAM), Tuberous Sclerosis-associated LAM (TS-LAM), Birt-Hogg-Dube (BHD), pulmonary arterial hypertension (PAH), and idiopathic Multicentric Castleman Disease (iMCD). Herdiscovery of the key involvement of the function of “tumor suppressor gene TSC2” was a paradigm-shifting observation in elucidating the cellular mechanisms of metabolic regulation in LAM and TS-LAM and directly led to clinical trials and ultimately FDA approval of rapalogs for clinical use and to current treatment of LAM and TS-LAM. Dr. Krymskaya’s further basic and translation study of LAM lead to promising combinational therapy which she currently test in clinic as a principal investigator of the SOS trial.
Faculty in the Pulmonary Division, led by Dr. Steven Albelda, interact closely with faculty from Thoracic Surgery, Oncology, and Pathology to conduct cutting edge diagnostic and therapeutic investigations related to lung cancer and malignant mesothelioma. Other members of the group include Drs. Anil Vachani, Andrew Haas, Melpo Christofidou-Solomidou, and Edmund Moon from Pulmonary, Drs. Sunil Singhal and Evgeniy Eruslavnov from Thoracic Surgery, Dr. Corey Langer from Oncology, and Drs. Leslie Litzky and Charu Desponde from pathology. Research from this group is supported by 2 NCI-funded Program Projects, a NIEHS Superfund Grant, NIH RO1 and KO8 grants, Industry, and Foundation support. The Abramson Cancer Center supports a Translational Center of Excellence in Lung Cancer Immunobiology and Immunotherapy.
The Thoracic Oncology Research Laboratory, led by Dr. Steven Albedla, is focusing on the design of new treatment strategies for lung cancer and mesothelioma based on the rapidly evolving disciplines of molecular biology, immunotherapy, and gene therapy.
Dr. Albelda’s research is translational in focus and includes animal models, work with human tumor samples, and the conduct of clinical trials. This work is primarily funded through a recently renewed Program Project from the National Cancer Institute and participation in a number of RO1 grants.
The tumor microenvironment is one area of active study. Studies are underway with the goals of 1) a better understanding of the biology of the tumor microenvironment with a focus on the immunuosuppressive activities of white blood cells and fibroblasts, 2) novel approaches to alter the tumor microenvironment to enhance immunotherapy including studying effects using COX-2 inhibitors, TGFbeta inhibitors, T-regulatory cell inhibitors., antibodies against B-cells, and chemotherapeutic drugs. A second area of interest in the lab is the use of adoptive T cell transfer to treat lung malignancies. Studies are underway to modify T cells in order to make them traffic more efficiently into tumors, to have better killing function, and to resist inactivation by the tumor microenvironment. A T cells targeting cancer-associated fibroblasts is being developed. In addition, Dr. Albelda is closely involved with a number of immunogene clinical trials at Penn using an adenovirus expressing the immune-activator interferon-alpha that is instilled into the pleural space of mesothelioma patients (in collaboration with Dr. Daniel Sterman) and T cells altered to attack the mesothelioma tumor target, mesothelin (in collaboration with Drs. Carl June and Andrew Haas).
Acute Respiratory Distress Syndrome and Sepsis Research Program
A multidisciplinary group of basic science and clinical investigators work together to study the pathogenesis, genetic basis and treatment of acute lung injury. A longstanding focus of this group has been oxidant injury and ischemia/reperfusion injury, while more recent work has established clinical and genetic risk factors for ARDS, identifying novel endotypes of the syndrome, and examining the role of neutrophils, red blood cells, glycans, and proteins in the development of lung injury. Translational research within the group is enhanced by collaborations with large sepsis, trauma, and transplant cohorts of critically ill patients. The group has a strong interest in emerging therapeutics and the potential for precision medicine. Key collaborations have been established with Dr. Vladimir Muzykantov from the Center for Targeted Therapeutics and Translational Nanomedicine, Drs. Dan Huh and Susan Margulies of the Department of Bioengineering, Dr. Ed Morrissey of Developmental Biology, and Dr. Scott Worthen from the Department of Neonatology. Within the Division, Drs. Christofidou-Solomidou, Mangalmurti, and DeLisser lead the bench research of lung injury while Drs. Christie, Meyer, Shashaty, and Reilly coordinate the clinical and translational ARDS research.
Dr. Nilam Mangalmurti's lab studies how both circulating and transfused red cells can modulate host lung inflammatory responses. In particular, I am interested in how the formation of novel red cell antigens during red blood cell storage can alter red cell-endothelial cell interactions and augment existing lung injury and predispose hosts to lung injury. The primary focus of the lab has been examining the role of the innate immune receptor, the Receptor for Advanced Glycation End-Products (RAGE), a multi-ligand receptor that is highly expressed in the lung and interacts with ligands on red blood cells.
Another focus of the lab is understanding how the lung endothelium can regulate the innate immune response. Specifically we are examining the role of novel programmed cell death pathways and endogenous immune mediators (danger signals) in the development and perpetuation of lung injury. Our lab utilizes human and murine cell culture models, in vivo animal models, microengineered human organ models (in collaboration with Dr. Dongeun Huh in Bioengineering) and clinical specimens (in collaboration with Drs. Jason Christie, Nuala Meyer and Michael Shashaty).
Epithelial Biology/ Lung Injury-Repair
Dr. Michael Beers heads a program aimed at studying the role of the distal lung epithelium in health and disease. The bench science program includes characterization of the biosynthetic pathways for surfactant system components, the role of cellular quality control pathways in the pathogenesis of parenchymal lung disease, and the function of surfactant in immunity and inflammation. Other members of the bench research group include Dr. Surafel Mulugeta and Dr. Arie Hawkins. In collaboration with the Center for Translational Lung Biology, a translational program in Interstitial Lung Disease has been developed which utilizes a patient data base, biospecimens, and lung explants for proof of concept studies and investigator-initiated questions. The program is funded by Veterans Administration Merit Review, an RO1 grant, and the Pulmonary Fibrosis Foundation.
Specific Projects include:
- Characterization of The Biosynthesis of Surfactant Protein C
- Protein Synthesis and Quality Control In the Lung Epithelium (UPR, ERAD, autophagy)
- Using SP-C and ABCA3 mutations to understand the pathogenesis of fibrotic lung diseases (Adult IPF patients and transgenic mouse models)
- Questions in Alveolar Epithelial Cell Biology (Lamellar Body genesis; endocytosis; regulated secretion)
- Lung Collectins and Host Defense
- Lung Collectins and Inflammation (Bleomycin, hyperoxia)
Developmental Lung Biology
Dr. Edward Morrisey leads a program focusing on the mechanisms driving early development of the lung and how such pathways regulate repair and regeneration of the postnatal respiratory system. Dr. Morrisey’s lab also has a strong focus on the development and regeneration of the cardiovascular system. His ultimate goal is to better understand how signaling and epigenetic pathways, regulate development and regeneration of the lungs and heart, leading to the development of new therapeutic approaches for lung and cardiac diseases.
Specific projects include:
- How Wnt signaling, non-coding RNAs, forkhead transcription factors, and epigenetic mechanisms regulate pulmonary and cardiovascular development.
- Defining how the pulmonary and cardiovascular systems co-develop i.e. how do the pulmonary vessels form?
- Determine how developmental pathways reactivated in the adult lung and whether they are critical to the repair and regeneration after injury or in disease states.
More than 50 lung transplants are performed at Penn every year. Penn is the coordinating site for the Lung Transplant Outcomes Group Consortium, the multicentered lung transplant cohort study of over 1600 subjects, currently funded by several R01 grants. Dr. James Lee is the Medical Director of the Lung Transplantation program. Faculty conducting research include Drs. Jason Christie, Vivek Ahya, James Lee, Mary Porteous, and Josh Diamond. Several clinical and translational projects are currently active. These are funded by NIH and Industry grants. A translational Program Project is being planned that will focus on acute graft dysfunction and use the newly developed program in extracorporeal lung perfusion headed by Dr. Edward Cantu of Surgery.
Specific faculty research interests include:
Jason Christie, M.D., MSCE
- Dr. Christie is the founder of the lung transplant outcomes group (LTOG), which is a multicentered cohort study the etiology and pathogenesis of acute lung injury following lung transplantation (termed primary graft dysfunction), with over 2200 subjects enrolled. His research focuses on the role of oxidative stress, coagulation/fibrinolysis, inflammatory and innate immune pathways in primary graft dysfunction. This line of research is funded by several R01 grants from NHLBI, focusing on genetic risks, innate immunity, autoimmunity to lung-specific minor histocompatibility antigens, obesity, regulatory T cell function, and the effects of smoke exposure on donors. .
Pulmonary Vascular Disease
For 15 years, the Kawut Lab has focused on the clinical epidemiology of pulmonary vascular disease and right ventricular function. In this role, the Lab has performed multicenter studies of clinical and genetic risk factors for a variety of pulmonary vascular diseases. Dr. Kawut was the first to show that female sex was a risk factor for portopulmonary hypertension, one of the only forms of pulmonary arterial hypertension with a sex predilection.
Moreover, one of the first high-throughput gene analyses in pulmonary hypertension was performed at the Kawut Lab, an effort that demonstrated that variants in aromatase and estrogen receptor genes were risk factors for portopulmonary hypertension. These studies have led to further investigation into the sexual dimorphism of pulmonary arterial hypertension.
Dr. Kawut 's group performed one of the first NIH-funded randomized clinical trials in pulmonary arterial hypertension. The Kawut Lab has also used clinical trial data from prior Phase III studies to examine the usefulness of end points in pulmonary arterial hypertension research and to demonstrate differential responsiveness to treatment among patients with different demographics and disease subtypes. Such an approach could one day lead to a "personalized medicine" approach to treating pulmonary vascular disease.
The Kawut Lab has had a longstanding interest in right ventricular morphology and response to disease. The group has studied the determinants (and impact) of right ventricular structure and function in healthy individuals and in those with advanced pulmonary vascular disease, showing that sex and race have important effects. Recent work has demonstrated that right ventricular hypertrophy in individuals without clinical cardiovascular disease at baseline increase the risk of heart failure or cardiovascular death. This group has also studied the impact of obstructive lung disease (e.g. COPD) on right ventricular morphology and function.