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Principal Investigator: TAMARA J. CASPARY
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $221,041
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
The objective of this proposal is to refine the understanding of the signaling mechanism(s) within the primary cilium in relation to polycystic kidney disease (PKD). Renal cysts interfere with kidney function and lead to major, long-term health complications. PKD and its related health complications result in a $7 billion per year economic burden in the United States so identifying molecular targets for treatment is a pressing unmet clinical need. Cilia, the slender protrusions on all renal cells, play key roles in cell signaling and cystogenesis but the details and underlying mechanism are ill-defined. Autosomal dominant polycystic kidney disease (ADPKD) is primarily due to mutations in the cilia-associated polycystin genes, PKD1 and PKD2. Normally, the polycystins function in cilia to suppress a pathway that promotes cysts. Identification of the molecular components of this pathway, termed the cilia-dependent cyst activator (CDCA), represents a clear molecular target for therapeutic strategies to counter ADPKD. The major challenge in working out the CDCA pathway, and in understanding ciliary signaling more generally, is that the tools in the field are too blunt. Mouse models typically delete genes, resulting in complete loss of both the ciliary and cellular pools of protein, making any interpretation of cilia-specific function impossible. We circumvented this challenge with the ciliary GTPase ARL13B, a proposed mediator of the CDCA. We removed ARL13B specifically from cilia by engineering a mouse expressing a cilia-excluded ARL13BV358A variant that retains all known biochemical activities. Arl13bV358A/V358A mice are viable and fertile yet display cystic kidneys indicating that it is the absence of ciliary ARL13B that is specifically critical to kidney cyst formation. Our goal in this proposal is to test our central hypothesis that ciliary ARL13B plays key roles in regulating kidney cystogenesis. The proposed work is important in forging fundamental knowledge of the identity and the timing of critical signaling mechanisms from within the primary cilium that could lead to therapeutic intervention for PKD.
Terms: <ADPKD><ARL3><ARL3 gene><Ablation><Adult Polycystic Kidney Disease><Autosomal Dominant Polycystic Kidney><Autosomal Dominant Polycystic Kidney Disease><Biochemical><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cilia><Clinical><Cyst><Cyst Fluid><Cystic Kidney Diseases><Cystic Renal Diseases><Cystic kidney><Data><Dissection><Dominant Polycystic Kidney Disease><Dysfunction><ESRD><Economic Burden><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endopeptidase PC2><Engineering><Exclusion><Frustration><Functional disorder><Future><GDP Dissociation Factor><GDP Dissociation Stimulators><GDP Exchange Factors><GDP-GTP Exchange Protein><GDP-GTP Reversing Factors><GTP GDP exchange factor><GTP Phosphohydrolases><GTPases><Gene Deletion><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Models><Genetic defect><Genets><Goals><Growth><Guanine Nucleotide Exchange Factors><Guanine Nucleotide Exchange Protein><Guanine Nucleotide Releasing Factors><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Guanyl-Nucleotide Exchange Factor><Guanyl-Nucleotide Releasing Factor><Health><Hedgehog (Hh) signal transduction pathway><Hepatic Disorder><Intracellular Communication and Signaling><Kidney><Kidney Cyst><Kidney Urinary System><Knowledge><Liver diseases><Mediator><Mice><Mice Mammals><Molecular><Morphology><Murine><Mus><Mutation><Neuroendocrine Convertase PC1><Neuroendocrine Convertase PC2><PC1><PC1 Endoprotease><PC1 Prohormone Convertase><PC2><PC2 Endoprotease><PC2 Prohormone Convertase><PC2 Protein><PC3 Endoprotease><PC3 Prohormone Convertase><Pathway interactions><Phenotype><Physiopathology><Play><Polycystic Kidney><Polycystic Kidney Diseases><Prohormone Convertase 1><Prohormone Convertase 2><Prohormone Convertase 3><Proinsulin Convertase 1><Proinsulin Convertase 2><Proprotein Convertase 1><Proprotein Convertase 2><Proprotein Convertase SPC3><Proteins><PubMed><Renal Cell><Renal Cyst><Renal function><Research><Role><SHH><SHH gene><Signal Transduction><Signal Transduction Systems><Signaling><Sonic Hedgehog><Testing><Therapeutic Intervention><Tissue Growth><United States><Variant><Variation><Work><biological signal transduction><exchange factor><experiment><experimental research><experimental study><experiments><forging><gene deletion mutation><genome mutation><guanosinetriphosphatase><hedgehog signaling><hedgehog signaling pathway><hepatic disease><hepatopathy><hh signaling pathway><insight><intervention therapy><kidney cell><kidney function><liver disorder><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mouse model><murine model><mutant><novel><ontogeny><optimal therapies><optimal treatments><pathophysiology><pathway><renal><smoothened signaling pathway><social role><therapeutic target><tool><trafficking>