Nephronophthisis (NPHP) is the most common genetic cause of end stage renal disease in infants, children, and young adults. NPHP is caused by a mutation in one of at least nine different genes (NPHP1 - NPHP9), accounting for less than 50% NPHP cases and indicating that many other disease loci remain unidentified. NPHP and other cystic kidney diseases are associated with defects in cilia. While the NPHP gene products (the nephrocystins) are localized to cilia, their functions in this sensory organelle remain largely unknown. The nematode Caenorhabditis elegans is a powerful model organism to study the roles of the nephrocystins in their native cellular environment. In C. elegans, NPHP-1 and NPHP-4 act globally to modulate ciliary development and morphogenesis in a cell-type specific manner. Human and worm nephrocystin-1 and nephrocystin-1 localize to the transition zone of cilia on renal epithelial cells and sensory neurons, respectively, suggesting an evolutionarily conserved role. Proposed studies in Aim 1 will define how NPHP-1 and NPHP-4 function at the ciliary transition zone. Proposed studies in Aim 2 will determine the role of the C. elegans NPHP2, NPHP8, and NPHP9 homologs. Proposed studies in Aim 3 will reveal genetic and functional interactions between the NPHP genes and known ciliopathy disease gene homologs. An understanding of human ciliary diseases such as Nephronophthisis relies on a complete understanding of ciliary components and of complex genetic and developmental interactions with modifier loci. These proposed studies will broaden our understanding of the nephrocystins and cilia biology at the genetic, molecular, cellular, and organismal levels. Such understanding is essential in order to identify the functions of the NPHP genes, their role in disease processes, and their potential as therapeutic targets.

Public Health Relevance

Cilia are motile or sensory organelles found on almost every non-dividing human cell. The mechanism of ciliary development is evolutionarily conserved in organisms ranging from alga, worms, flies, fish, mouse, to human. Recent studies have revealed that defects in cilia are linked to human cystic kidney diseases such as Nephronophthisis (NPHP), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive PKD, Bardet-Biedl Syndrome (BBS), and Meckel Gruber Syndrome (MKS). The nematode Caenorhabditis elegans is an exceptional animal model system for the study of cilia-related human disease genes. Many of the genes required for the formation, maintenance, and function of C. elegans cilia have human counterparts that, when mutated, cause diseases with renal pathologies. The study is designed to use the powerful molecular genetic tools of C. elegans to model Nephronophthisis, the most common genetic cause of end stage renal disease in infants, children, and young adults. Project Narrative Cilia are motile or sensory organelles found on almost every non-dividing human cell. The mechanism of ciliary development is evolutionarily conserved in organisms ranging from alga, worms, flies, fish, mouse, to human. Recent studies have revealed that defects in cilia are linked to human cystic kidney diseases such as Nephronophthisis (NPHP), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive PKD, Bardet-Biedl Syndrome (BBS), and Meckel Gruber Syndrome (MKS). The nematode Caenorhabditis elegans is an exceptional animal model system for the study of cilia-related human disease genes. Many of the genes required for the formation, maintenance, and function of C. elegans cilia have human counterparts that, when mutated, cause diseases with renal pathologies. The study is designed to use the powerful molecular genetic tools of C. elegans to model Nephronophthisis, the most common genetic cause of end stage renal disease in infants, children, and young adults.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK074746-09
Application #
8717637
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Wang, Juan; Silva, Malan; Haas, Leonard A et al. (2014) C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr Biol 24:519-25
Rajendran, Lawrence; Bali, Jitin; Barr, Maureen M et al. (2014) Emerging roles of extracellular vesicles in the nervous system. J Neurosci 34:15482-9
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
Jauregui, Andrew R; Nguyen, Ken C Q; Hall, David H et al. (2008) The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol 180:973-88