Cilia serve as motile or sensory devices on most eukaryotic cells surface and play an essential role in the proper formation of a diversity of organs in development. Ciliary assembly via intraflagellar transport (IFT) and sensory transduction capabilities are highly conserved in all ciliated organisms. With rapid advancements in the positional cloning of human disease genes in the past decade, a wide variety of disorders, such as autosomal dominant polycystic kidney disease (ADPKD), Joubert syndrome (JBST), Bardet-Biedl syndrome (BBS), nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), and autosomal recessive polycystic kidney disease (ARPKD), have been characterized molecularly as cilia-related diseases, now known collectively as ciliopathies. The establishment and maintenance of ciliary function are clearly essential for the well-being of an organism. Consistent with the ubiquitous presence of cilia, many ciliopathies occur as syndromic disorders that affect multiple organs, including the kidney, liver, limb, eye, and central nervous system. Despite the physiological and clinical relevance of cilia, the core machinery that regulates cilia biogenesis and function as well as the connection between the disease gene function and pathology remain largely elusive. Three small GTPase Arls (ADP-ribosylation factor (Arf)-like proteins), Arl3, Arl6/Bbs3, and Arl13B, have been implicated in either human ciliopathies or vertebrate ciliopathy models, and also confirmed to be conserved ciliary proteins in all examined ciliated organisms. Small GTPases act as key molecular switches in diverse membrane- and cytoskeleton-related cellular processes. However, the roles of Arl family members are poorly defined. Because the study of the connections between cilia formation and sensory function and disease are prohibitively difficult in humans and in mammalian model organisms, alternative experimental systems are necessary. C. elegans enables the exploration of these questions in living animals., The highly conserved ciliopathy candidates, ciliogenesis pathway, and cilia sensory function make Caenorhabditis elegans a powerful model for characterizing the physiological roles of ciliopathy genes in their native cellular environments. This proposal is to test the central hypothesis that the ciliopathy Arls act as key regulators in a concerted manner in the context of cilia. The proposed studies have great potential to unveil breakthroughs in cilia research in the near future, and would provide seminal information about how cilia biogenesis and sensory function are regulated in their native environment, shed light on the etiologies of ciliopathies, and potentially provide novel targets for disease diagnosis and treatment.

Public Health Relevance

Defects in cilia biogenesis or function contribute to a wide spectrum of human diseases, now collectively called as ciliopathies. This proposal is designed to use the simple but powerful genetic model C. elegans to characterize the concerted roles of three ciliopathy small GTPases (Arl3, Arl6, and Arl13B) in the context of cilia and their correlation to the pathology of human ciliopathies. Our proposed studies will broaden the understanding of cilia development and function in normal and pathological states and provide seminal insights into the roles of the three ciliary Arls and their effectors in disease processes, and their potential as therapeutic targets.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Rasooly, Rebekah S
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Mayo Clinic, Rochester
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