Research Areas of the Hertzano Lab
Our laboratory studies the coordinated regulation of gene expression in the various cell types of the inner ear to understand the molecular programs that drive inner ear development and function. Led by a surgeon-scientist – Ronna Hertzano, MD PhD – Department of Otorhinolaryngology Head and Neck Surgery, and Anatomy and Neurobiology and Institute for Genome Sciences (IGS) – both the laboratory research and discussions are translational in nature. Our overarching goal is to develop new therapeutics to prevent and treat genetic and acquired hearing loss. Our highly collaborative work ranges from genetics and functional genomics to imaging and hearing/balance physiology using a variety of in vitro and in vivo models. In addition to performing cutting edge research, our goal is to assist in training the next generation of scientists and clinician-scientists. Our laboratory’s home is in the 2nd floor of the University of Maryland School of Medicine Health Science Research Facility 3, nested within the IGS.
Below are the three main focus areas of our work:
Cell-type Specific Molecular Pathways in Inner Ear Development
We specialize in identifying transcription factors and gene regulatory networks with key roles in the development and function of the ear. This reveals new genes and pathways important for hearing restoration.
Sex Differences in Hearing and the Molecular Basis of Acquired Hearing Loss
We work to elucidate the critical differences in hearing physiology and susceptibility to noise between males and females. In doing so, we hope to build a path towards therapeutics.
Tools for Sharing, Visualizing, and Analyzing Multi-omic Data
We built the gene Expression Analysis Resource – umgear.org – a portal for multi-omic data visualization, analysis and sharing. Recently, an extension of the project is used to support data visualization and analysis for the BRAIN initiative (nemoanalytics.org).
Cell-Type Specific Molecular Pathways Directing Inner Ear Development
The RFX Transcription Factors - an opportunity to unravel the underpinnings of hair cell terminal differentiation
Capitalizing on our cell type-specific protocols for analysis of the inner ear, we obtained pure populations of auditory and vestibular hair cells (HCs) from newborn inner ears. Bioinformatic analysis of the promoters of the HC-enriched transcripts pointed to the ciliogenic RFX transcription factors as the main regulators of the HC-specific transcriptomes. To validate this novel finding, we generated double conditional mutants for Rfx1 and Rfx3 and discovered that in their absence, the outer hair cells die within 12 hours from the onset of hearing. We are currently studying the mechanisms by which RFX transcription factors support hair cell development and maintenance.
Illuminating outer hair cell development and survival via the Ikzf2/helios regulatory network
Age-related hearing loss is a worldwide epidemic characterized by the progressive loss of hair cells, particularly outer hair cells (OHCs). Despite the importance of hair cells, the mechanisms underlying the specification of progenitor cells to functional inner versus outer hair cells are poorly understood. In a highly collaborative study using a combination of methods that range from genetic analysis, single cell RNA-seq, in vivo gene delivery, imaging, and electrophysiology, we recently identified IKZF2 as a critical regulator of the terminal maturation of the outer hair cells (published in Nature, 2018). Importantly, we discovered that viral gene transfer of Ikzf2 to inner HCs (IHCs) can induce a partial molecular and functional conversion of IHCs to OHCs. We continue to study IKZF2 to illuminate outer hair cell development and function.
Understanding the role of cochlear mesenchyme cells through the lens of Pou3f4
While most of the research in the ear field is focused on the cochlear sensory epithelium, little is known about the otic mesenchyme cells, which are the most prevalent cell population in the developing inner ear. Mutations in the mesenchyme-expressed transcription factor Pou3f4 cause deafness in humans and mice, indicating that these understudied cells are important for normal hearing. Importantly, Pou3f4 is essential for normal endocochlear potential and is crucial for spiral ganglion neuron (SGN) axonal guidance, fasciculation, and supports SGN survival. In this collaborative project, we study the mechanisms by which Pou3f4 support inner ear development and function.
Sex Differences in Hearing and the Molecular Basis of Acquired Hearing Loss
Google ‘how old are your ears’! The range of frequencies in which adults have functional hearing is significantly reduced compared to children, and by age 70, half of the population has a hearing loss that warrants amplification. Sensorineural hearing loss is a natural process which begins at the basal turn of the cochlea, the area responsible for detection of higher frequencies. According to the WHO, there are currently 450 million people worldwide with disabling hearing loss, a number that will increase to 900 million by 2050 – much of which is a result of noise exposure. Similarly, noise induced hearing loss (NIHL) is the second most common health issue afflicting military veterans and a medical problem affecting 5% of the adult population worldwide. We work to build the blueprint of the molecular changes in the different cell types of the ear following noise exposure, which is critical for rational drug design. In addition, we look at the impact of biological sex on hearing physiology and susceptibility to noise-induced hearing loss, with the hopes that our research may aid in the development of therapeutics in the future.
Developing Tools for Sharing, Visualization, and Analysis of Multi-Omic Data
Bigger even than the unending struggle to handle the increasing scale of data exported by omics instruments is the challenge of creating responsive, scalable visualization and analysis tools for the data they produce. Importantly, high throughput multi-omic analyses are now the workhorse for discovery in biological sciences. Many biologists lack the training and background in informatics required for the meaningfully interrogation of the data generated. Even if trained, the added effort to download data from central repositories to simply look up the expression of a gene is significant, particularly for large single cell-based data. We built the gene Expression Analysis Resource – umgear.org – a portal for multi-omic data visualization, analysis and sharing. Recently, an extension of the project is used to support data visualization and analysis for the BRAIN initiative (nemoanalytics.org).
We are grateful for the financial support provided by the Action on Hearing Loss, Department of Defense, Hearing Restoration Project, National Institute on Deafness and Other Communication Disorders, National Institute of Mental Health, United States – Israel Binational Science Foundation, and the Carolyn Frenkil Foundation, who have made these projects possible.
