Over the course of my career, my research has focused on understanding the control of cell division and cell and tissue regeneration. My graduate work using DNA tumor (papilloma) viruses and initial post-doctoral work on the pRb tumor suppressor protein laid the foundation for inquiries into the molecular mechanisms that control stem and progenitor cell function, which I have pursued since I started my own lab.
My later post-doctoral work in Dr. David Warburton's lab enabled me to become immersed in lung cell biology and lung physiology, which interested me so much and that I decided to focus my stem/progenitor cell queries on the process of lung regeneration. The fact that so many human lung diseases can be considered the result of a failure to properly regenerate adds extra impetus to this work.
In my lab we are particularly interested in lung progenitor cell turnover and the exhaustion of the regenerative capacity of lung, either through disease or aging. We have done this by examining the role of telomerase in lung epithelial cell function and were the first to show that telomerase activity increases in developing alveolar epithelial type 2 cells (AEC2) and in hyperoxic adult AEC2 repair phase following hyperoxic injury. We went on to show that telomerase activity is expressed by a discrete subpopulation of AEC2 during injury repair, which led us to hypothesize that the function of telomerase may be key to understanding how lung epithelial progenitor cells survive injury in order to facilitate regeneration.
This hypothesis was extended when we were able to show that knockdown of telomerase activity, coupled with acute telomere shortening, has a profound impact on the ability to lung epithelium to maintain homeostasis and to mount a regeneration response. Our most recent work has focused on examining the molecular events downstream of acute telomere shortening that cause this failure. We have also begun to explore methods for using exogenous stem cells, specifically amniotic fluid stem cells (AFSC), as both a tool to help us understand how the cellular milieu of the aged lung changes over time and to explore possible, stem cell-directed therapeutic approaches to lung regeneration. In addition, we have developed a novel mouse model, the SPCTK mouse, which allows us to eliminate AEC2 under controlled conditions as a tool for examining and contrasting subsequent regeneration in youthful and aged animals.
University of Southern California
Navarro S, Reddy R, Lee J, Warburton D, Driscoll B. Inhaled resveratrol treatments slow ageing-related degenerative changes in mouse lung. Thorax. 2017 Jan 9. pii: thoraxjnl-2016-208964. doi: 10.1136/thoraxjnl-2016-208964. [Epub ahead of print]
Navarro S, Driscoll B. Regeneration of the Aging Lung: A Mini-Review. Gerontology. 2016 Nov 9. [Epub ahead of print]
Trecartin A, Danopoulos S, Spurrier R, Knaneh-Monem H, Hiatt M, Driscoll B, Hochstim C, Al-Alam D, Grikscheit TC. Establishing Proximal and Distal Regional Identities in Murine and Human Tissue-Engineered Lung and Trachea. Tissue Eng Part C Methods. 2016 Nov;22(11):1049-1057.
Im D, Shi W, Driscoll B. Pediatric Acute Respiratory Distress Syndrome: Fibrosis versus Repair. Front Pediatr. 2016 Mar 30;4:28. doi: 10.3389/fped.2016.00028. Review.
Wieck MM, Spurrier RG, Levin DE, Mojica SG, Hiatt MJ, Reddy R, Hou X, Navarro S, Lee J, Lundin A, Driscoll B, Grikscheit TC. Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease. PLoS One. 2016 Feb 10;11(2):e0148323. doi: 10.1371/journal.pone.0148323.
Garcia O, Hiatt MJ, Lundin A, Lee J, Reddy R, Navarro S, Kikuchi A, Driscoll B. Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair. Am J Respir Cell Mol Biol. 2016 Mar;54(3):319-30. doi: 10.1165/rcmb.2014-0246OC.
Garcia O, Carraro G, Turcatel G, Hall M, Sedrakyan S, Roche T, Buckley S, Driscoll B, Perin L, Warburton D. Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS One. 2013 Aug 13;8(8):e71679. doi: 10.1371/journal.pone.0071679.
Lundin A, Driscoll B. Lung cancer stem cells: progress and prospects. Cancer Lett. 2013 Sep 10;338(1):89-93. doi: 10.1016/j.canlet.2012.08.014. Review.
Garcia O, Buckley S, Navarro S, Driscoll B, Warburton D. Modulating the alveolar milieu to enhance resolution of fibrotic lung injury. Proc Am Thorac Soc. 2012 Jul;9(3):117-9. doi: 10.1513/pats.201201-013AW.
Driscoll B, Kikuchi A, Lau AN, Lee J, Reddy R, Jesudason E, Kim CF, Warburton D. Isolation and characterization of distal lung progenitor cells. Methods Mol Biol. 2012;879:109-22. doi: 10.1007/978-1-61779-815-3_7.
Garcia O, Carraro G, Navarro S, Bertoncello I, McQualter J, Driscoll B, Jesudason E, Warburton D. Cell-based therapies for lung disease. Br Med Bull. 2012;101:147-61. doi: 10.1093/bmb/ldr051. Review.
Buckley S, Shi W, Carraro G, Sedrakyan S, Da Sacco S, Driscoll BA, Perin L, De Filippo RE, Warburton D. The milieu of damaged alveolar epithelial type 2 cells stimulates alveolar wound repair by endogenous and exogenous progenitors. Am J Respir Cell Mol Biol. 2011 Dec;45(6):1212-21. doi: 10.1165/rcmb.2010-0325OC.
Jackson SR, Lee J, Reddy R, Williams GN, Kikuchi A, Freiberg Y, Warburton D, Driscoll B. Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L898-909. doi: 10.1152/ajplung.00409.2010.
Jackson S, Williams GN, Lee J, Baer J, Warburton D, Driscoll B. A modified technique for partial pneumonectomy in the mouse. J Investigative Surgery. J Invest Surg. 24:81-86, 2011
Jackson S, Lee J, Reddy R, Williams GN, Kikuchi A, Freiberg Y, Warburton D, Driscoll B. Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol. 300:L898- L909, 2011
Buckley S, Shi W, Carraro G, Sedrakyan S, Da Sacco S, Driscoll B, Perin L, de Filippo RE, Warburton D. The Milieu of Damaged AEC2 Stimulates Alveolar Wound Repair by Endogenous and Exogenous Progenitors. Am J Respir Cell Mol Biol. 45:1212-1221, 2011
Lee J, Reddy R, Barsky L, Scholes J, Chen H, Shi W, Driscoll B. Lung alveolar integrity is compromised by telomere shortening in telomerase null mice. Am J Physiol Lung Cell Mol Physiol, 296:L57-L70, 2009
Gupte VV, Ramasamy SK, Reddy R, Lee J, Weinreb PH, Violette SM, Guenther A, Warburton D, Driscoll B, Minoo P, Bellusci S. Overexpression of Fibroblast Growth Factor 10 (FGF10) Both During The Inflammatory and The Fibrotic Phases Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice. Am J Respir Crit Care Med. 180:424- 436, 2009
Warburton D, Perin L, DeFillipo R, Carraro G and Driscoll B. Endogenous versus exogenous stem/progenitor cells for lung injury repair and regeneration. Proc Am Thorac Soc. 5:703-706, 2008
Carraro G, Perin L, Sedrakyan S, Giuliani S, Tiozzo C, Lee J, Turcatel B, De Langhe SP, Driscoll B, Bellusci S, Minoo P , Atala A, De Filippo R, Warburton D. Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages. Stem Cells, 26:2902-2911, 2008
Lee J, Reddy R, Barsky L, Weinberg K, Driscoll B. Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia. Am J Physiol Lung Cell Mol Physiol. 290:L685-L694, 2006
Reddy, R., Buckley, S., Barsky, L., Weinberg, K., Anderson, K.D., Warburton, D. and Driscoll, B. "Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells." American Journal of Physiology Lung Cellular & Molecular Physiology 286:L658-L667, 2004.
Buckley, S, Shi, W., Driscoll, B., Ferrario, A., Anderson, K.D. and Warburton, D. "BMP-4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells." Am J Physiol Lung Cell Mol Physiol. 286:L81-L86, 2004.
Buckley, S, Driscoll, B, Shi, W, Anderson KD, and Warburton, D. "Migration and gelatinases in cultured fetal, adult, and hyperoxic alveolar epithelial cells." American Journal of Physiology Lung Cellular & Molecular Physiology 281:L427-L434 (2001)
Driscoll, B, Buckley, S, Bui, KC, Anderson KD, and Warburton, D. "Telomerase in alveolar epithelial development and repair." American Journal of Physiology 279 (Lung Cellular & Molecular Physiology): L1191-L1198 (2000)
Driscoll, B., A. T'Ang, Y.H. Hu, C.L. Yan, Y. Fu, Y. Luo, K.J. Wu, S. Wen, X.H. Shi, L. Barsky, K. Weinberg, A.L. Murphree, Y.K. Fung. "Discovery of a regulatory motif that controls the exposure of specific upstream cyclin-dependent kinase sites that determine both conformation and growth suppressing activity of pRb." J. Biol. Chem. 274: 9463-9471 (1999)
Analysis of the impact of natural aging and premature aging on lung health and function.
Analysis of lung regeneration using a novel mouse model developed in my lab in which mild, moderate or severe lung injury can be induced in a precisely controlled manner.
Analysis of the impact of stem cell and pharmaceutical therapies on the inevitable deterioration due to aging and premature aging of the lung.
Functional characterization of stem cells isolated from pediatric patients suffering severe cardiopulmonary injury and/or failure.
Lung Health & Function Research Overview
My lab investigates the impact of aging and, in the case of younger individuals, premature aging, on lung health and function. We are particularly interested in how aging affects the ability of lung progenitor cells to resist disease and function in injury repair. We are also interested in determining how these cells interact with other types of cells, including stem cells, that exist within the lung or come into the lung from the circulatory system, and how this interaction can stimulate or impede the aging process and the repair of lung injury. In all these studies we analyze cellular pathways related to oxidative stress, inflammation and changes in the cell cycle.
We have made several discoveries of key markers for premature aging that show up in the lungs of younger individuals that carry specific genetic mutations, which we hope will lead to the design of intervention therapies, including the use of specialized stem cells that modify the lung environment. Recently my lab developed an in vivo model for the study of lung injury. This model can be “fine-tuned” so that lung injury can be induced to mild, moderate or severe levels.
With a clinical collaborator, Kim Bui,MD, we have also begun to examine a unique population of stem cells isolated from pediatric patients that survive severe cardiopulmonary injury. We hope to determine if these cells can be used therapeutically in the treatment of pediatric heart and lung failure.
Analysis of the functional impact of natural aging and premature aging due to chromosomal telomere shortening.
These studies have provided the following novel information for the field:
- Telomerase is upregulated in lung epithelial cells during regeneration following injury
- Telomerase dysfunction and telomere shortening inhibit lung injury repair by inducing epithelial cell growth arrest, rather than proliferation, in response to regenerative stimuli
- Lung epithelial cells from telomerase/telomere dysfunctional animals exhibit significant and chronic DNA damage even in absence of injury
- Telomere shortening and subsequent chromosomal destabilization have a direct impact on mitochondrial integrity, which in turn induces epithelial cell senescence
- The increase in arrested, damaged and senescent epithelial cells in aging lung are conducive to the development of fibrosis
- Naturally aged lung and lung prematurely aged due to telomerase/telomere dysfunction share a number of functional characteristics and changes in key signaling pathways, particularly those that regulate the cell cycle and the response to oxidative stress
Analysis of the impact of stem cell and pharmaceutical therapies on the inevitable deterioration due to lung aging.
These studies make use of the knowledge acquired using our naturally and prematurely aged models. We are hoping to design therapeutic approaches to the buildup of senescent cells and the increased levels of inflammation that occur as the lung ages. We are currently analyzing the impact of systemic versus lung-specific administration of mesenchymal stem cells, as well as certain drugs, on the baseline integrity of the lung. These treatments are being assessed for their ability to influence lung injury response, the lung inflammatory environment and pulmonary function.
Analysis of lung regeneration using a novel model developed in my lab in which mild, moderate or severe lung injury can be induced in a precisely controlled manner.
These studies have shown us that a myriad of cell types and factors respond to distal lung epithelial cell injury, and have thus provided us with a number of targets, including pulmonary and circulating mesenchymal and immune cells, that could be modified in order to stimulate robust lung regeneration.
Functional characterization of stem cells isolated from pediatric patients suffering severe cardiopulmonary injury/failure.
With my clinical collaborator, Dr. Kim Bui, we have begun to examine a unique population of stem cells isolated from pediatric patients that survive severe cardiopulmonary injury. Dr. Bui has shown that these cells are a rare, non-tumorigenic stem cell that can be cultured from the peripheral blood of patients who have suffered such significant lung and/or heart injury that they require extra-corporal membrane oxygenation (ECMO) therapy. My lab has shown that these cells are significantly more attracted to sites of lung injury than normal, bone marrow-derived stem cells. We are currently working to functionally characterize these cells in the context of in vivo lung injury order to determine if the ECMO patient-derived cells can be used therapeutically in the treatment of pediatric heart and lung failure.
Telomerase is upregulated in lung epithelial cells during regeneration following injury and telomerase dysfunction and telomere shortening inhibit lung injury repair by inducing epithelial cell growth arrest, rather than proliferation, in response to regenerative stimuli.
Lung epithelial cells from telomerase/telomere dysfunctional animals exhibit significant and chronic chromosomal and mitochondrial DNA damage even in absence of injury.
Naturally aged lung and lung prematurely aged due to telomerase/telomere dysfunction share a number of functional characteristics and changes in key signaling pathways, particularly those that regulate the cell cycle and the response to oxidative stress.
NIH/NHLBI R01 Alveolar epithelial cells: development and repair (PI: Driscoll)
This grant supports ongoing work on the impact of telomere shortening, natural aging and premature aging on lung injury and repair.
CIRM Bridges to Stem Cell Award (Driscoll Co-PI with PI Eversole-Cire)
This grant supports the training of Pasadena City College Biotechnology students in stem cell biology and hands-on training in stem cell laboratory techniques in labs located at THE UNIVERSITY OF SOUTHERN CALIFORNIA, Children’s Hospital Los Angeles and CalTech.
CIRM Stem Cell Training Grant (Driscoll Co-PI with Co-PI Warburton)
This grant supports training basic research post-doctoral fellows and clinical research fellows at of Children’s Hospital Los Angeles, THE UNIVERSITY OF SOUTHERN CALIFORNIA and CalTech in stem cell biology and hands-on training in labs doing stem cell laboratory research.
- Doyle-Hilligoss Award, University of San Diego
- The Shaffer Lecture, University of San Diego
- Partnership Award, Pasadena City College