Exploring the role of extracellular matrix components in TRP polycystin ciliary localization and function PKD2 encodes a transient receptor potential polycystin (TRPP) channel receptor protein found in non-motile, primary cilia of mammalian cells. In humans, PKD2 mutations result in Autosomal Dominant Polycystic Kidney Disease (ADPKD). In the nematode Caenorhabditis elegans, the polycystin-2 homolog, PKD-2, localizes to the primary cilia of male-specific sensory neurons (CEMs and RnBs in the head and tail respectively) where it is required for male mating behaviors. Given the ancient and evolutionarily conserved role for polycystin-2 in cilia, C. elegans will be used as a model to identify new genes required for ciliary receptor localization. Mutants were isolated from a forward genetic screen for PKD-2: GFP ciliary localization (Cil) defects. The cil-2(my2) mutants exhibit excess unusual PKD-2 accumulation at the ciliary base, cilium proper, and around the distal dendrite. Three-factor and deficiency mapping, whole genome sequencing, and single gene rescue experiments have determined that the cil-2(my2) allele is a mutation in the gene mec-5. MEC-5 is a unique collagen protein found in the extracellular matrix (ECM) surrounding touch receptor neurons. In touch receptor neurons (TRNs), MEC-1, MEC-5, and MEC-9 are found in the ECM, play a role in mechanosensation, and may localize degenerin/epithelial sodium channels (DEG/ENaCs) along the TRN. Preliminary data indicates that mec-1 and mec-9 regulate PKD-2::GFP localization in male-specific sensory neurons. Therefore current research will determine how these ECM proteins regulate localization and channel properties of the PKD-2 TRP polycystin channel. These studies will shed light on how sensory receptors like PKD-2 are targeted to cilia, and may advance the understanding and treatment of ADPKD.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder. Children of a person with ADPKD have a 50% chance of developing this disease. Further, 50% of affected persons, progress to end stage renal disease. My studies of PKD-2 protein localization to primary, non-motile cilia will add to th base of knowledge and extend further research of this disease towards the mechanosensory aspect of polycystins and the impact of extracellular matrix on ion channel localization.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1-GRB-G (M1))
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Mcbryde, Kevin D
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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