July 18-19, 2011
Proteostasis refers to a collection of cellular processes handling protein folding, misfolding, unfolding, and degradation. Proteostasis is fundamental to cell survival and function, and critical for all organs and tissues. The cellular ability to maintain proteostasis declines with age, making it likely that the public health and economic impact of proteostasis dysfunction will increase as the population ages. The lung uniquely must contend with constant mechanical stress and diverse forms of environmental stress, both of which constantly threaten normal protein folding. To meet this challenge, the lung is equipped with a robust proteostasis network that prevents protein misfolding and repairs or recycles damaged proteins. Recent studies have indicated that alterations in proteostasis in the lung can result in a loss of protein function (e.g. insufficient amounts of active protein) in cystic fibrosis, and/or a gain of toxic function (e.g. mutant surfactant proteins overburdening proteostasis pathways), and cell death in lung tissues.
To explore proteostasis management as a new therapeutic paradigm for pulmonary disease, research is needed to delineate mechanisms coupling protein folding and degradation to the development of lung diseases and their associated complications.
In response to this scientific opportunity in lung research, the Division of Lung Diseases in the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop, “Malfolded Protein Structure and Proteostasis in Lung Diseases,” on July 18 and 19, 2011. The workshop focused on identifying gaps in scientific knowledge with respect to proteostasis and lung disease, discussing new research advances and opportunities in protein folding science, and highlighting novel technologies with potential therapeutic applications for the diagnosis and treatment of lung disease. The “Malfolded Protein Structure and Proteostasis in Lung Diseases” Workshop report was published by the American Journal of Respiratory and Critical Care Medicine, (Vol. 189, No. 1 (2014), pp. 96-103).
- Define the mechanisms leading to altered proteostasis in the lung (e.g. genetic, environmental, inflammation, co-morbid conditions), and the mechanisms coupling alterations in the proteostasis machinery to lung diseases (ALI, COPD, asthma, pulmonary fibrosis) and their common associated complications (e.g. skeletal muscle wasting).
- Investigate how the proteostasis network is affected by aging, obesity and other co-morbid factors in lung diseases. Develop a mechanistic understanding of how cumulative proteotoxic stress might accelerate or ameliorate age or co-morbidity-related changes in proteostasis capacity, including their contributions to cell death and impaired lung regeneration. For example, do mechanisms underlying muscle dysfunction resulting from sepsis, pneumonia, or COPD differ in older or obese individuals and do these individuals respond differently to therapies?
- Develop pertinent cell and animal based experimental model systems to investigate proteostatis function in vivo and in cell based models of lung disease. For example, invertebrate models (e.g. the nematode Caenorhabditis elegans) could be used to investigate genetic mechanisms of oxidative stress in lung disease. Patient-derived cell lines (primary, iPS and organoid cultures) could be used to apply and/or develop tools to assess the function of molecular chaperones, and/or activation of signaling responses (HSR, UPR, mitoUPR, UPS, ALP, ASR, HAT/HDAC) critical to the etiology or exacerbation of lung disease. Mice expressing proteostasis reporters could be used to monitor the function of proteostasis networks in health and in models of lung disease.
- Improve sampling from patients with lung diseases (blood, airway and alveolar lining fluid and muscles) to assess proteostatic machinery alterations in disease and response to therapy. Evaluate the efficacy of specific interventions targeting metagenomic, UPR, UPS, and autophagy mechanisms, to improve lung pathophysiology and disease outcomes.
- Delineate proteostasis-coupled mechanisms by which ALI, sepsis, and other critical illnesses that originate in the lung induce morbidity and mortality in extra-pulmonary target organs (e.g. skeletal muscle, kidney, and heart).
- Define how environmental stresses including infection, hypoxia, hypercapnia, sleep disordered breathing and sleep deficiency, and environmental contaminants modulate proteostasis networks, as potential mechanisms of tissue damage, injury, and repair.
- Develop new pharmacologic tools (e.g. small molecules) that target proteostatic pathways relevant to lung disease. Investigate the efficacy of targeted therapies aimed to manage proteostasis in the early and late stages of lung disease. Are there opportunities to slow or halt lung disease progression through proteostasis-targeted therapies?
- Apply modern bioinformatic tools and approaches incorporating the proteasome into systems biology models of lung disease(s).
- As a critical component of all of these research priorities, it is recommended that future efforts take an integrated approach:
- Provide a platform to facilitate interdisciplinary interactions between experts in proteostasis and pre-clinical and clinical lung disease.
- Develop resources for lung researchers to apply and/or develop new technologies in proteostasis science, including mass spectrometry to monitor the onset and progression of diseases. A systems based approach will be required to map these data to one another (developing a proteostatic network model) and to link these results to the genetic and natural history of disease progression.
- Utilize ongoing clinical trials such as ARDSNet, IPFNet, and others to assess the relationship between proteostasis health and related organ disorders, including muscle strength in ICU patients.
- William Balch, PhD, The Scripps Research Institute
- Jacob I. Sznajder, MD, Northwestern University
- Esther Barreiro, MD, PhD, IMIM-Hospital del Mar, UPF, CIBERES, Barcelona, Spain.
- Michael F. Beers, MD, University of Pennsylvania Medical Center
- Ivor J. Benjamin, MD, FACC, FAHA, Medical College of Wisconsin
- Gregory R Budinger, MD, Northwestern University
- Timothy Scott Blackwell, MD, Vanderbilt University
- Navdeep S Chandel, PhD, Northwestern University
- Augustine Choi, MD Brigham and Women's Hospital
- Ana Maria Cuervo MD, PhD, Albert Einstein College of Medicine
- Laura Dada, PhD, Northwestern University
- Daniel Finley, PhD, Harvard Medical School
- Margaret S Herridge, MD, University of Toronto, Canada
- Jeffrey R. Jacobson, MD, University of Illinois at Chicago
- Randal Kaufman, PhD, Sanford Burnham Medical Research Institute
- Landon S. King, MD, Johns Hopkins University
- Richard I. Morimoto, PhD, Northwestern University
- Allan Powe, PhD, Vertex Pharmaceuticals, Inc.
- Jean-Marc D. Quach, MBA, Alpha-1 Project (TAP)
- Kathryn Ann Radigan, MD, Northwestern University
- Sigrid Veasey, MD, University of Pennsylvania
- Neeraj Vij, MS, PhD, Johns Hopkins University School of Medicine
- Allan M. Weissman, MD, National Cancer Institute
- Bishow Adhikari, PhD, Division of Cardiovascular Sciences (DCVS) NHLBI
- Thomas Croxton, MD, PhD, Division of Lung Diseases (DLD) NHLBI
- Dorothy Gail, PhD, DLD NHLBI
- Weiniu Gan, PhD, DLD NHLBI
- Andrea Harabin, PhD, DLD NHLBI
- Aaron D. Laposky, PhD, DLD NHLBI
- Lisa Postow, PhD, DLD NHLBI
- Susan Schlegel, PhD, DLD NHLBI
- Gail Weinmann, MD, DLD NHLBI
- Mahadev Murthy, PhD, MBA, Division of Aging Biology (DAB) NIA
- Felipe Sierra, PhD, DAB NIA
- Jose M. Velazquez, PhD, DAB NIA
- John P. Williams, PhD, DAB NIA