Institutional Career Development Core

摘要

ABSTRACT The proposed NIDCR KL2 application is to provide support for generating innovative translational science and questions that will lead to a mentored K series grant award. With the strong support of my mentoring team alongside robust institutional foundations from both Children’s Hospital of Philadelphia and the University of Pennsylvania Institute for Translational Medicine and Therapeutics, this project for career development will advance our scientific knowledge of craniofacial development in neuroscience and tooth mineralization. Tooth enamel and neuronal development are both highly complex and integrated systems that occur at similar time points during fetal growth. Unfortunately, many neurological disorders have limited biomarkers for identifying the presence or severity prior to preventative strategies or therapeutic interventions. Recently, evidence suggests that genetic, epigenetic, or environmental changes affecting enamel formation may reflect alterations in behavior. It is also common that among the craniofacial disorders, both neurons and ameloblasts (enamel cells) exhibit similar dysregulated patterns in vesicle transport and membrane turnover, though details of these pathways have not been well investigated. These findings, therefore, hold a fascinating promise that tooth enamel formation can be used as a biomarker for altered neurodevelopment through a common vesicle transport mechanism affecting membrane turnover in the ameloblasts and neurons. The TBC1 Domain-Containing Kinase (TBCK) syndrome is a rare craniofacial disorder that is characterized by its spectrum of neurogenetic phenotypes, ranging from developmental delay, low muscle tone, coarse facial features, and encephalopathy with altered periventricular white matter. In addition to the neurological deficits of tbck mice mimicking the human phenotypes, recent findings have demonstrated a tooth enamel phenotype in the tbck heterozygous knockout mice, indicating this mouse to be an excellent model for understanding the link between these two tissue types and enamel as a biomarker for neurologic development. We therefore propose to investigate the hypothesis that vesicle transport, specifically the PI3K-Akt signaling pathway, is disrupted in teeth (as it is in neurons), such that the tooth enamel reflects aberrant neuronal development observed in the mice and patients lacking TBCK. This hypothesis will be tested with the following specific aims: Aim 1: Characterize the tooth phenotypes of both patients and mice with deficiencies in the Tbck gene. This aim will test whether humans exhibit similar enamel phenotypes to those of tbck-/- mice. Aim 2: Determine whether aberrant vesicle transport via PI3K-Akt signaling occurs in the enamel organ of mice deficient in Tbck. This aim will test whether disrupted enamel formation is due to PI3k-Akt in the absence of tbck. Completion of this project will provide an excellent foundation for future translational work in the crossover of tooth and neurological development and will direct our understanding of the mechanistic underpinnings that drive the dynamic intracellular processes that regulate vesicle transport.