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Background : Airway diseases such as asthma, chronic bronchitis, and cystic fibrosis cause morbidity and mortality in large numbers of people. Model systems in small animals and in cell culture systems have proved valuable in illuminating disease mechanism and providing leads for new treatment approaches for these diseases. In addition, clinical research studies have also provided important complimentary information.

My laboratory has a dual infrastructure encompassing clincial research space in the Airway Clinical Research Center on the 13 th floor of Moffitt hospital and bench space in HSE13. This dual infrastructure allows me to pursue research in airway diseases, especially asthma, in a research program that is heavily focused on human asthma but which also incorporates molecular analysis of biospecimens from human subjects in my bench laboratory as well as experimental approaches that take advantage of cell- and animal-based model systems. My laboratory has a mix of M.D. and Ph.D scientists who share interests in mechanism-oriented clinical research in airway disease.

Major goals: (i) to define abnormalities in epithelial cell function in the airway that contribute to mucin upregulation on the one hand and to abnormal epithelial mesenchymal signaling on the other; (ii) to characterize the physiology of the normal airway mucus gel and to explore mechanisms of formation of pathologic gel in disease; (iii) to determine the mechanisms for why some asthmatics are susceptible to severe asthma attacks (exacerbations) while others are resistant.

On-going Research:

Periostin as a mediator of epithelial mesenchymal signaling: In genome wide expression studies of epithelial cell from asthmatic subjects and healthy controls, we discovered that periostin is markedly upregulated in asthma. This led me to establish a research program in my lab that is focused on understanding the biology of periostin in the airway in health and disease. We have continued to use human based samples in these studies, but we have extended our approaches to include periostin over-expressing epithelial cells and studies in periostin knockout mice. To date, our work shows that periostin is expressed at the protein level by airway epithelial cells and is secreted basally into the airway mucosal matrix. In addition to autocrine and paracrine signaling events that are alter epithelial cell function (Including effects to upregulate TGFbeta), we have found that periostin has important effects on fibrillar proteins in the matrix. Specifically, we have found that periostin binds and cross-links collagens (and probably fibronectin as well). For these studies we have used rheology-based measures of elastic modulus as an indicator of cross-linking. Thus epithelial derived periostin is secreted into the matrix where it can regulate matrix stiffness. We are excited to continue studies of periostin because of the broad implications of these effects for the pathophysiology of airway and parenchymal lung diseases.

Multimeric lectins as cross linkers of mucin polymers: Mucus hypersecretion is an important clinical characteristic of airway disease, and pathologic mucus plugs are an important cause of airflow obstruction in acute severe asthma. Together with collaborators at University College Dublin, we hypothesize that the formation of mucus plugs occurs because of abnormal cross-linking of mucin polymers. We specifically hypothesize that galactose-binding lectins are important mucin cross linkers, because galactose is a common monosaccharide in mucin glycans. We are actively investigating this hypothesis and we are fortunate that we can collect fresh sputum samples from healthy and asthmatic volunteers in our clinical research space and then analyze the sputum in our bench lab. Our analyses include immunoblotting for mucins and lectins and rheology-based measures of mucus viscoelasticity. This work has the potential to identify new approaches for treatment of mucus plug formation in the airway, a clinical problem for which is there is great unmet need.

Histoblood group antigens as susceptibility factors for asthma exacerbation: Some asthmatic experience frequent asthma attacks (exacerbations) and some are quite resistant. The reasons for this are not clear but may relate to susceptibility to the lower airway complications of upper respiratory tract infection with viruses. For the past 5 years we have been investigating the possibility that histoblood group antigens are susceptibility factors for exacerbation prone asthma. In a case control study we have found that the airway epithelial expression of the H antigen (found in subject with blood type O) is associated with an increased odds of being prone to asthma exacerbations. We are now investigating whether rhinovirus, a common cause of the asthma exacerbation, binds to blood group antigens (in particular to the H antigen).

Biomarkers of molecular phenotypes of asthma: In collaboration with Prescott Woodruff at UCSF and investigators at Genentech, my lab has contributed to studies which have identified two distinct molecular phenotypes of asthma – one of which is characterized by Th2 cytokine-driven disease and one of which is not. Two major questions arise from this work, which was based on gene expression profiling of airway epithelial ells. One is whether we can identify blood-based biomarkers of Th2 status in asthma. This is an area of active investigation. The second is to figure out the molecular underpinning of Th2-low asthma. This second question will be difficult because the Th2 low asthmatic subgroup is likely a heterogonous collection of multiple subgroups. However, my lab has a strong commitment to continue to build a high quality biobank of human samples (airway tissues, blood, DNA) from well-characterized asthmatics to enable ongoing association studies that will attempt to match specific molecular characteristics to specific clinical phenotypes.