Primary cilia are small projections present on the surface of most vertebrate cell types. Defects in these structures have been associated with a growing list of disorders including Bardet-Biedl Syndrome, Polycystic Kidney Disease, and Nephronophthisis, among others. Though several developmental signaling pathways are known to be regulated by cilia, a clear understanding of the extent of their involvement in signal transduction remains elusive. Notch signaling, in particular, may be associated with cilia and may, therefore, underlie ciliopathy phenotypes. We hypothesize that defects in primary cilia result in perturbation of Notch signaling and that this regulation results in disruption of associated developmental processes. Specifically, we hypothesize that cilia-dependent defects in Notch underlie pancreatic defects and diabetes, which are prevalent in ciliopathy patients. Using a zebrafish model and in vitro systems, we propose to test this hypothesis by two specific aims. First, we will investigate the mechanistic link between disruption of ciliary function and perturbation of Notch signaling during development. We will then investigate a role for cilia in pancreatic development and function. The proposed research builds on Dr. Zaghloul's previous training in developmental genetics and ciliary biology. She will be guided by mentors with expertise in the areas of molecular mechanisms and genetics of diabetes, pancreatic development and function, and zebrafish development. The expertise gained as a result of this Career Development Award will poise Dr. Zaghloul to launch a fully independent career investigating cililary regulation of complex phenotypes. The research studies outlined here will establish a zebrafish model of ciliary dysfunction with a specific focus on pancreatic phenotypes. The overall proposal is strengthened by: 1) a specific focus on Notch signaling and an associated phenotype that has been largely unexplored in the context of cilia, and 2) a strong team of mentors with recognized expertise investigating these phenotypes. An improved understanding of the molecular mechanisms underlying these phenotypes may suggest common links between ciliopathies and common traits and provide new insights into the treatment of these conditions.
Pancreatic defects and diabetes are prevalent in patients with mutations in genes that make up primary cilia, tiny projections present on the surface of most cell types. The proposed studies seek to investigate how primary cilia regulate developmental processes that contribute to pancreatic development and the onset of diabetes.
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|Liu, Yangfan P; Tsai, I-Chun; Morleo, Manuela et al. (2014) Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators. J Clin Invest 124:2059-70|
|Leitch, Carmen C; Zaghloul, Norann A (2014) BBS4 is necessary for ciliary localization of TrkB receptor and activation by BDNF. PLoS One 9:e98687|