Cilia are cellular organelles that are important for human development, organ function, and sensation. Defects in cilia formation or function results in devastating human diseases or ciliopathies, including autosomal dominant polycystic kidney disease (ADPKD). ADPKD affects 1/400-1000 individuals, often resulting in end- stage renal disease. In humans, mutations in the polycystin-1 or polycystin-2 receptor-channel complex cause ADPKD. Despite the profound medical importance of cilia in human health, how cilia are specialized in form and function remains poorly understood. This proposed research is focused on uncovering fundamental principals of cilia biology not possible in human studies or easily studied in vertebrate model systems. C. elegans is a transparent, multicellular animal with specialized sensory cilia, features that enable in vivo imaging that is unprecedented in its simplicity and reproducibility. We have developed the tools and reagents to study polycystin localization and function in C. elegans. We will employ genetic, molecular, imaging, biochemical, and electrophysiological approaches to address three specific aims. First, we will dissect polycystin signaling pathways. Next, we will determine the molecular details of mechanisms regulating polycystin localization, focusing on the roles of phosphoinositides and tubulin post-translational modifications. Finally, we will identify new genes regulating PKD-2 localization using transgenic animals that are hypersensitive to neuronal RNAi. This multidisciplinary approach will provide a comprehensive picture of the molecules that influence polycystin channel assembly and trafficking, and will provide critical insight to ciliary receptor trafficking in general. Thus these studies will have important implications in human diseases such as ADPKD in which cilia play an important and central role.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting 1/400-1000 individuals, and having no treatment or cure. Several human genetic disorders, including ADPKD, share two common features: ciliary localized gene products and kidney cysts. Given that it is prohibitively difficult in humans to study the connection between ciliary protein function, localization, and disease, alternative experimental systems are necessary. In C. elegans it is feasible to study the roles of human disease gene homologs in cilia formation, morphogenesis, and signaling. This proposal is aimed at understanding the molecular mechanisms controlling the subcellular trafficking of the C. elegans ADPKD gene products.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059418-14
Application #
8465215
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
2011-09-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
14
Fiscal Year
2013
Total Cost
$312,925
Indirect Cost
$103,037
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Schroeder, Nathan E; Flatt, Kristen M (2014) In vivo imaging of Dauer-specific neuronal remodeling in C. elegans. J Vis Exp :e51834
Sengupta, Piali; Barr, Maureen M (2014) New insights into an old organelle: meeting report on biology of cilia and flagella. Traffic 15:717-26
Rajendran, Lawrence; Bali, Jitin; Barr, Maureen M et al. (2014) Emerging roles of extracellular vesicles in the nervous system. J Neurosci 34:15482-9
Schroeder, Nathan E; Androwski, Rebecca J; Rashid, Alina et al. (2013) Dauer-specific dendrite arborization in C. elegans is regulated by KPC-1/Furin. Curr Biol 23:1527-35
O'Hagan, Robert; Piasecki, Brian P; Silva, Malan et al. (2011) The tubulin deglutamylase CCPP-1 regulates the function and stability of sensory cilia in C. elegans. Curr Biol 21:1685-94
Morsci, Natalia S; Haas, Leonard A; Barr, Maureen M (2011) Sperm status regulates sexual attraction in Caenorhabditis elegans. Genetics 189:1341-6
Morsci, Natalia S; Barr, Maureen M (2011) Kinesin-3 KLP-6 regulates intraflagellar transport in male-specific cilia of Caenorhabditis elegans. Curr Biol 21:1239-44
Bae, Young-Kyung; Kim, Eunsoo; L'hernault, Steven W et al. (2009) The CIL-1 PI 5-phosphatase localizes TRP Polycystins to cilia and activates sperm in C. elegans. Curr Biol 19:1599-607

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