Research interest

Stereocilia are a bundle of cylindrical F-actin protrusions developed on the apical surface of inner ear hair cells and function as biological mechanosensors to detect sound, acceleration and gravity. The long-term goal of my research is to elucidate the molecular mechanisms that permit stereocilia to be developed from tiny microvilli, equipped with mechanotransduction channel complexes and structurally stable for years. There are currently no clinically effective treatments to regenerate or restore stereocilia although degeneration of stereocilia is a process that often accompanies sensorineural hearing loss caused by genetic variations, aging, drugs and noise exposure, which is one of the reasons why sensorineural hearing loss is often irreversible. Understanding the protein dynamics in stereocilia will be a basis to (1) formulate therapeutic strategies for sensorineural hearing loss and (2) provide experimental data necessary for genetic diagnosis of patients suspected of having hereditary hearing loss.

My research carrier initially focused on the dynamic regulation of actin cytoskeleton. Single-molecule microscopy, which I learned at Kyoto University, has been a powerful tool to elucidate the dynamics of actin regulatory proteins, such as CapZ, the Arp2/3 complex and DIAPH1. Single-molecule microscopy poses two challenges of interest to me: (1) solving a clinical problem and (2) elucidating the in vivo protein dynamics, especially in stereocilia. To accomplish the first challenge, I have been collaborating in an international research effort with Japanese and Korean researchers. I have worked on the pathophysiology of DIAPH1 variants associated with human deafness DFNA1 and used single-molecule microscopy to visualize abnormal actin elongation activity of mutant DIAPH1. The second challenge started at NIDCD/NIH. Under the mentorship of Dr. Thomas B. Friedman (NIDCD/NIH) and Dr. Hari Shroff (formerly NIBIB/NIH, currently Janelia Research Campus), I developed a workflow for single-molecule microscopy in stereocilia of live hair cells and started analyses of active cargo transport driven by unconventional myosins and the molecular turnover of stereocilia components.

Currently, I am utilizing my single-molecule microscopy technique to visualize trafficking of MYO7A, which are essential for localizing the mechanotransduction complex at stereocilia tips. I am also expanding the imaging target to other unconventional myosins whose variants are associated with human hearing loss and to actin and regulatory proteins, which are replenished maintaining the entire architecture of stereocilia. My single-molecule microscopy will be a novel tool for analyzing the normal and aberrant behavior of proteins in stereocilia, improving the efficacy and reliability of genetic diagnoses based on experimental data and formulating therapeutic strategies for sensorineural hearing loss. In addition, approaches developed in my study will be generally useful outside the field of hearing research to analyze the pathophysiology of mutant human genes affecting other organ systems.