Lawrence Ostrowski, PhD

Research Associate Professor

Specialty Areas: Structure and Function of Cilia; Diseases of Cilia and Mucociliary Clearance; Gene Therapy of CF and Primary Ciliary Dyskinesia

Research Focus:

The overall focus of research in my laboratory is to improve the diagnosis and treatment of airway diseases, especially those that result from impaired mucociliary clearance. Mucociliary clearance is the process by which inhaled pathogens and particulate matter are swept out of the lungs by the coordinated beating of the cilia that line the airways (Figure 1). In particular, our efforts focus on the diseases cystic fibrosis and primary ciliary dyskinesia, two inherited diseases caused by mutations that impair mucociliary clearance and lead to recurrent lung infections. The work in our laboratory ranges from basic studies of ciliated cells and the proteins that make up the complex structure of the motile cilia (Figure 2), to translational studies of new drugs and gene therapy vectors. Our laboratory uses a number of model systems, including traditional and inducible animal models, in vitro culture of differentiated mouse and human airway epithelial cells, and direct studies of human tissues. We also use a wide range of experimental techniques, from studies of RNA expression and proteomics to measuring ciliary activity in cultured cells and whole animals.

Figure 1a. An electron micrograph of human cilia. Photograph courtesy of Kimberly Burns, CF Center Histology Core Director. Figure 1b. Diagram and an electron micrograph of a cross-section through a cilium, illustrating the basic “9+2” structure of axonemal doublets. Note the dynein arms that provide the force for ciliary motility. Figure 1c. A schematic of a single dynein arm at the protein level, showing some of the more than 300 proteins required to assemble a cilium. Proteins highlighted in red are mutated in some cases of primary ciliary dyskinesia.
Figure 1a. An electron micrograph of human cilia. Photograph courtesy of Kimberly Burns, CF Center Histology Core Director. Figure 1b. Diagram and an electron micrograph of a cross-section through a cilium, illustrating the basic “9+2” structure of axonemal doublets. Note the dynein arms that provide the force for ciliary motility. Figure 1c. A schematic of a single dynein arm at the protein level, showing some of the more than 300 proteins required to assemble a cilium. Proteins highlighted in red are mutated in some cases of primary ciliary dyskinesia.

Selected Bibliography:

  1. Lin J, Yin W, Smith MC, Song K, Leigh MW, Zariwala MA, Knowles MR, Ostrowski LE, Nicastro D. Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia. Nat Commun. 2014 Dec 4;5:5727. doi: 10.1038/ncomms6727. PubMed PMID: 25473808; PubMed Central PMCID: PMC4267722.
  2. Knowles MR, Ostrowski LE, Leigh MW, Sears PR, Davis SD, Wolf WE, Hazucha MJ, Carson JL, Olivier KN, Sagel SD, Rosenfeld M, Ferkol TW, Dell SD, Milla CE, Randell SH, Yin W, Sannuti A, Metjian HM, Noone PG, Noone PJ, Olson CA, Patrone MV, Dang H, Lee HS, Hurd TW, Gee HY, Otto EA, Halbritter J, Kohl S, Kircher M, Krischer J, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Zariwala MA. Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med. 2014 Mar 15;189(6):707-17. doi: 10.1164/rccm.201311-2047OC. PubMed PMID: 24568568; PubMed Central PMCID: PMC3983840.
  3. Knowles MR, Ostrowski LE, Loges NT, Hurd T, Leigh MW, Huang L, Wolf WE, Carson JL, Hazucha MJ, Yin W, Davis SD, Dell SD, Ferkol TW, Sagel SD, Olivier KN, Jahnke C, Olbrich H, Werner C, Raidt J, Wallmeier J, Pennekamp P, Dougherty GW, Hjeij R, Gee HY, Otto EA, Halbritter J, Chaki M, Diaz KA, Braun DA, Porath JD, Schueler M, Baktai G, Griese M, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Hildebrandt F, Shendure J, Omran H, Zariwala MA. Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. Am J Hum Genet. 2013 Oct 3;93(4):711-20. doi: 10.1016/j.ajhg.2013.07.025. Epub 2013 Sep 19. PubMed PMID: 24055112; PubMed Central PMCID: PMC3791252.
  4. Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA; Genetic Disorders of Mucociliary Clearance Consortium. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012 Dec 20. PubMed PMID: 23261302; PubMed Central PMCID: PMC3542458.
  5. Grubb BR, O’Neal WK, Ostrowski LE, Kreda SM, Button B, Boucher RC. Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease. Am J Physiol Lung Cell Mol Physiol. 2012 Jan 15;302(2):L238-47. doi: 10.1152/ajplung.00083.2011. Epub 2011 Oct 14. PubMed PMID: 22003093; PubMed Central PMCID: PMC3349361.
  6. Ostrowski LE, Yin W, Rogers TD, Busalacchi KB, Chua M, O’Neal WK, Grubb BR. Conditional deletion of dnaic1 in a murine model of primary ciliary dyskinesia causes chronic rhinosinusitis. Am J Respir Cell Mol Biol. 2010 Jul;43(1):55-63. doi: 10.1165/rcmb.2009-0118OC. Epub 2009 Aug 12. PubMed PMID: 19675306; PubMed Central PMCID: PMC2911571.