PROJECT SUMMARY
The form of an organ defines its function. How simple epithelial tissues give rise to the complex forms of mature
organs is a fundamental question in developmental biology with important implications in disease and
regenerative medicine. A beautiful example is the remodeling of a simple embryonic epithelium to form the three
semicircular canals (SCC) of the inner ear. Their intricate form is required for sensing balance and acceleration
and is conserved across all jawed vertebrates. SCCs can develop abnormally in congenital syndromes such as
LAMM, CHARGE and Alagille syndrome, for unknown reasons. The mechanisms underlying healthy
development are poorly understood. My preliminary findings indicate that local synthesis of a hyaluronan-rich
extracellular matrix (ECM) is important in SCC development. In the proposed research, I will determine how this
ECM helps generate mechanical forces in SCC morphogenesis in zebrafish (Aim1). I will use next-generation
single-cell sequencing to identify genes involved in the patterning of an active ECM (Aim2) and to identify and
characterize the role of other ECM components involved in SCC development (Aim3). The novel molecular-
mechanical principles revealed from this study will be widely applicable to other morphogenetic events involving
an active ECM and topological epithelial remodeling. Moreover, as these processes are disrupted in many
congenital diseases and ear disorders, my findings will improve our understanding of these diseases.
The proposed research draws on 1) my training in quantitative cell biology in a development context, 2) the new
skills acquired in my post-doctoral research, including zebrafish research and imaging of the developing organ
at single-cell resolution, and 3) my K99 training plan to implement automated image analysis, in vivo biophysical
measurements, modeling, and single-cell sequencing and analysis. To fulfil my aims, I will receive mentorship
from Drs. Sean Megason, Tim Mitchison, L. Mahadevan and Allon Klein, whose combined expertise in zebrafish
development, gene-editing, biophysics, quantitative imaging, modeling and single-cell RNA sequencing will give
me the training I need to commence my independent research program. To facilitate my career development
during the mentored K99 phase, I will take relevant courses and maintain collaborations for both fundamental
and translational research, present my work at meetings, publish my research, write grants, and gain further
experience in management and mentoring students to formulate my own mentoring style. I will greatly benefit
from the experience, track record and regular feedback from my co-mentors to start my own laboratory.
My long-term career goal is to head an inter-disciplinary research program to investigate the mechanical and
molecular basis of morphogenesis and to use the insights I develop to advance translational research. I’ve made
significant progress towards this goal in the form of research experience, successful collaborations and
publications. The K99 award will give me access to the additional training and expertise I need to successfully
transition to independence.
