Eugene Chang

Eugene Chang

Associate Professor, Otolaryngology
Vice Chair, Academic Affairs - Otolaryngology
Associate Professor, Clinical Translational Sciences
Associate Professor, Neurosurgery
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Department Affiliations
(520) 626-6673

Research Interest

Dr. Chang’s research is divided into three areas.Cystic fibrosis (CF) research: Dr. Chang is investigating the role of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the pathogenesis of chronic sinusitis. He published the first animal model of CF sinus disease, and has characterized novel therapies including gene therapy vectors and CFTR potentiators in improving CF sinus disease in both animals and humans.Sinus microbiome research: the “microbiome” is the microbial community that is present in the human body. The sinonasal cavities have traditionally been thought to be sterile cavities, but new research is beginning to elucidate the vast number of microbial communities that populate our sinus. With this knowledge, we are investigating how our current therapies can influence this microbial population and prevent sinus disease.Impact of the upper and lower airway: as otolaryngologists, our focus has been in the airway of the head and neck. Dr. Chang has been investigating how the upper airway can influence disease of the lower airway, and vice versa. This research can influence the understanding of common diseases of the lower airway, such as asthma and chronic obstructive pulmonary disease (COPD).Dr. Chang receives active funding research support from the NIH, and the Cystic Fibrosis Foundation.


Ruf, R. G., Xu, P., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Brophy, P. D., Berkman, J., Gattas, M., Hyland, V., Ruf, E., Schwartz, C., Chang, E. H., Smith, R. J., Stratakis, C. A., , Weil, D., et al. (2004). SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8090-5.

Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans.

Lacruz, R. S., Smith, C. E., Moffatt, P., Chang, E. H., Bromage, T. G., Bringas, P., Nanci, A., Baniwal, S. K., Zabner, J., Welsh, M. J., Kurtz, I., & Paine, M. L. (2012). Requirements for ion and solute transport, and pH regulation during enamel maturation. Journal of cellular physiology, 227(4), 1776-85.

Transcellular bicarbonate transport is suspected to be an important pathway used by ameloblasts to regulate extracellular pH and support crystal growth during enamel maturation. Proteins that play a role in amelogenesis include members of the ABC transporters (SLC gene family and CFTR). A number of carbonic anhydrases (CAs) have also been identified. The defined functions of these genes are likely interlinked during enamel mineralization. The purpose of this study is to quantify relative mRNA levels of individual SLC, Cftr, and CAs in enamel cells obtained from secretory and maturation stages on rat incisors. We also present novel data on the enamel phenotypes for two animal models, a mutant porcine (CFTR-ΔF508) and the NBCe1-null mouse. Our data show that two SLCs (AE2 and NBCe1), Cftr, and Car2, Car3, Car6, and Car12 are all significantly up-regulated at the onset of the maturation stage of amelogenesis when compared to the secretory stage. The remaining SLCs and CA gene transcripts showed negligible expression or no significant change in expression from secretory to maturation stages. The enamel of CFTR-ΔF508 adult pigs was hypomineralized and showed abnormal crystal growth. NBCe1-null mice enamel was structurally defective and had a marked decrease in mineral content relative to wild-type. These data demonstrate the importance of many non-matrix proteins to amelogenesis and that the expression levels of multiple genes regulating extracellular pH are modulated during enamel maturation in response to an increased need for pH buffering during hydroxyapatite crystal growth.

Faucett, E. A., Larsen, B. T., Khan, R., Chiu, A. G., & Chang, E. H. (2016). A Diagnostic Dilemma: Multiple Primary Intracranial Tumors Without Vestibular Schwannomas. The Annals of otology, rhinology, and laryngology, 125(11), 938-942.

Sinonasal schwannomas with intracranial extension are exceedingly rare, with only 7 cases reported in the literature. Schwannomas can be isolated or multiple and are commonly associated with familial disorders such as neurofibromatosis 2 (NF 2) or familial schwannomatosis or in sporadic cases seen in sporadic schwannomatosis. Nearly all people with NF2 older than 30 years of age will have the hallmark of bilateral vestibular schwannomas (VS). This case highlights a reported case of an adult with separate primary intracranial tumors. We review the diagnostic criteria of NF2 and schwannomatosis, a recently described third variant of neurofibromatosis. In this case, we incorporate family history, histopathology, and the pathophysiology of both disorders to help determine a diagnosis for this patient.

Williams, A. L., Calton, J. B., Chiu, A. G., & Chang, E. H. (2015). Dead or alive: Deoxyribonuclease I sensitive bacteria and implications for the sinus microbiome. American journal of rhinology & allergy.

Recently, there has been tremendous interest in the sinus microbiome and how it relates to disease. However, a lack of a standardized sample collection and DNA extraction methods makes comparison of results across studies nearly impossible. Furthermore, current techniques fail to identify which components of the microbiome are actually alive within the host at the time of sampling.

Sinn, P. L., Cooney, A. L., Oakland, M., Dylla, D. E., Wallen, T. J., Pezzulo, A. A., Chang, E. H., & McCray, P. B. (2012). Lentiviral vector gene transfer to porcine airways. Molecular therapy. Nucleic acids, 1, e56.

In this study, we investigated lentiviral vector development and transduction efficiencies in well-differentiated primary cultures of pig airway epithelia (PAE) and wild-type pigs in vivo. We noted gene transfer efficiencies similar to that observed for human airway epithelia (HAE). Interestingly, feline immunodeficiency virus (FIV)-based vectors transduced immortalized pig cells as well as pig primary cells more efficiently than HIV-1-based vectors. PAE express TRIM5α, a well-characterized species-specific lentiviral restriction factor. We contrasted the restrictive properties of porcine TRIM5α against FIV- and HIV-based vectors using gain and loss of function approaches. We observed no effect on HIV-1 or FIV conferred transgene expression in response to porcine TRIM5α overexpression or knockdown. To evaluate the ability of GP64-FIV to transduce porcine airways in vivo, we delivered vector expressing mCherry to the tracheal lobe of the lung and the ethmoid sinus of 4-week-old pigs. One week later, epithelial cells expressing mCherry were readily detected. Our findings indicate that pseudotyped FIV vectors confer similar tropisms in porcine epithelia as observed in human HAE and provide further support for the selection of GP64 as an appropriate envelope pseudotype for future preclinical gene therapy studies in the porcine model of cystic fibrosis (CF).Molecular Therapy - Nucleic Acids (2012) 1, e56; doi:10.1038/mtna.2012.47; published online 27 November 2012.