This proposal outlines a detailed plan for providing the investigator with the scientific training and career developmen skills to ensure a successful postdoctoral training period. His training will be mentored by Drs. Chad Pearson (sponsor) and Lee Niswander (co-sponsor) at the University of Colorado-School of Medicine. The scientific training will focus on how levels of the second messenger ion calcium (Ca2+) are regulated within subcellular signaling structures called cilia, and, in turn, how cilia Ca2+ levels impact ciia structure. Cilia are ubiquitous and evolutionarily conserved appendages that are present on nearly every cell in the human body. Since defects in cilia contribute to a plethora of devastating and currently intractable developmental disorders, this research is expected to improve our basic understanding of cilia biology and inform future ciliopathy therapies. To investigate the relationship between cilia and Ca2+, the investigator has established the hypothesis that cilia Ca2+ levels directly regulate cilia length and that the basal body (BB), which is a small microtubule structure that sits at the base of cilia, regulates the flow of Ca2+ into and out of ciia. To test this this hypothesis, the investigator proposes to accomplish two aims.
In Aim1, the investigator will use Ca2+ imaging, optopharmacological manipulation of ciliary Ca2+, and genetic ablation of ciliary Ca2+ levels to directly test how ciliary Ca2+ levels impact cilia lengt. The results from this aim will resolve a fundamental question in cilia biology that is related to how the global manipulation of Ca2+ is able to specifically alter cilia length.
In Aim2, the investigator will use similar tools to define how structurally defective BBs alter the flow of Ca2+ into and out of cilia at rest and during signaling events in olfactory sensory neurons. The results from these experiments will illuminate the BB as a novel regulator of ciliary Ca2+ signaling, which will open up a new area of inquiry for the investigator to pursue. In conjunction with a strong mentoring team, the investigator has also established professional developmental goals, such as manuscript preparation, attendance at national conferences and formal coursework in the areas of microscopy, digital image analysis and grant writing to ensure that the scientific training is translated into a future career as an independent investigator.
Ciliopathies are a devastating class of inherited disorders that have wide-ranging effects on nearly every organ system, including the brain, kidneys, lungs and skeletal system; ciliopathies arise due to defects in tiny sub-cellular structures known as cilia. The goal of this proposal is to explore my hypothesis that an inability to properly regulate the level of calcium ions (Ca2+) within cilia alters their structure and function. Testing this hypothesis may illuminate future ciliopathy therapies designed to specifically manipulate cilia Ca2+ levels.
| Galati, Domenico F; Sullivan, Kelly D; Pham, Andrew T et al. (2018) Trisomy 21 Represses Cilia Formation and Function. Dev Cell 46:641-650.e6 |
| Galati, Domenico F; Mitchell, Brian J; Pearson, Chad G (2016) Subdistal Appendages Stabilize the Ups and Downs of Ciliary Life. Dev Cell 39:387-389 |
| Bayless, Brian A; Galati, Domenico F; Junker, Anthony D et al. (2016) Asymmetrically localized proteins stabilize basal bodies against ciliary beating forces. J Cell Biol 215:457-466 |
| Hudish, Laura I; Galati, Domenico F; Ravanelli, Andrew M et al. (2016) miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling. Development 143:2292-304 |
