[K08] Define the mechanisms through which STK33 regulates multiciliated cells
Ente: National Heart Lung and Blood Institute
Scadenza: 2031-02-28
Importo max: 166.752 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
The following proposal outlines a 5-year career training plan that will prepare Dr. Andrew Berical to be an
independent physician-scientist and leader in the field of airway epithelial functional genomics. Motile cilia are
found throughout the human body, most notably on multiciliated cells (MCCs) in the conducting airway.
Individuals with primary ciliary dyskinesia (PCD) have inherited variants in any one of more than 50 genes that
regulate the structure or function of cilia, leading to a lifetime of chronic cough, recurrent infections and
respiratory failure. Due to the complexity of the MCC molecular program and limited disease-relevant platforms,
there are no targeted therapies available for PCD. An improved understanding of fundamental MCC biology and
the availability of a human-based platform would have enormous implications for the PCD field. Dr. Berical’s
long-term vision is to utilize pluripotent stem cell-based techniques to understand how specific genes regulate
airway epithelial homeostasis and how gene variants lead to the initiation of airway diseases such as PCD, CF,
asthma, COPD and IPF. Dr. Berical presents preliminary data suggesting a recently described serine-threonine
kinase (STK33) has a fundamental role in the MCC developmental program. STK33 deletion results in 1) fewer
MCCs, 2) fewer cilia per cell, 3) an abnormal ciliary structure and 4) reduced ciliary beat frequency. In this
proposal, Dr. Berical aims to understand the mechanism by which STK33 effects the MCC molecular program
to create this highly irregular phenotype. Leveraging key training opportunities through his collaborators and
scientific advisory committee, he will 1) precisely characterize the STK33-dependent MCC defects using time
course single cell RNA-sequencing to pinpoint when, during MCC differentiation, STK33 exerts its effect, 2)
identify STK33 downstream targets and effector molecules and 3) determine the in vivo ramifications of STK33
loss on the engraftment, differentiation and function of airway epithelial cells. Following this investigation of the
STK33-dependent regulation of MCC biology, Dr. Berical then expands these methods to probe the functions of
a curated list of high priority ciliary kinases of unknown function. This work will provide much needed insight into
the MCC molecular program and develop an essential platform for the interrogation of genes of unknown function
in the airway epithelium, applicable to the genetically heterogeneous PCD, as well as other airway diseases. Dr.
Berical has 80% protected time from his department to accomplish these aims under the guidance of his mentors
Drs. Finn Hawkins and Darrell Kotton at the Center for Regenerative Medicine at Boston University/Boston
Medical Center. He has assembled a remarkable team of advisors with diverse expertise to assist in his career
development and scientific research. Dr. Berical details a comprehensive training plan that includes experiential
tra
Istituzione: BOSTON UNIVERSITY MEDICAL CAMPUS
PI: Andrew Berical
Progetto: 1K08HL181385-01A1
Settori: National Heart Lung and Blood Institute
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