The long-term goal of this proposal is to develop therapeutic strategies for the treatment of two human diseases, Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and Dent disease, which result from loss-of-function mutations in the gene encoding the inositol 5-phosphatase OCRL. Lowe syndrome is a severe X-linked disorder characterized by reabsorption defects in the kidney proximal tubule (renal Fanconi syndrome), mental retardation and congenital cataracts. Dent disease is another X-linked disorder in which the clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. While it is known that the main function of OCRL, an enzyme expressed by all cells of the body, is to dephosphorylate two bilayer phospholipids, PI(4,5)P2 and PI(3,4,5)P3 (members of the phosphoinositide family) at the 5 position of their inositol ring, the mechanisms through which a defect in the catalytic activity of this enzyme cause disease, and specifically kidney disease, remain unclear. The objective of this project is to elucidate such mechanisms. Strong evidence indicates that a main function of OCRL is to avoid accumulation of its substrates on membranes of the endocytic pathway. It is hypothesized that the resulting inappropriate intracellular accumulation of these lipids, primarily PI(4,5)P2, leads to ectopic actn nucleation and abnormal traffic and sorting of membrane proteins along the endocytic pathway. This effect is expected to have a dramatic impact on proximal tubule cells due the massive endocytic activity occurring at their actinrich apical pole. In this proposal we plan to elucidate he physiological function of the intracellular phosphoinositide pools controlled by OCRL, to determine how such pools regulate actin nucleation and endosomal traffic, and to establish how these events specifically affect the function of kidney proximal tubule cells in model mouse and cell lines.

Public Health Relevance

This project will shed light on mechanisms of two severe kidney diseases and will thus represent a critical step towards their cure. The information acquired with this project will be relevant to the therapy of other conditions resulting from the impairment of kidney proximal tubule cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Mullins, Christopher V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Anatomy/Cell Biology
Schools of Medicine
New Haven
United States
Zip Code
Messa, Mirko; Fernández-Busnadiego, Rubén; Sun, Elizabeth Wen et al. (2014) Epsin deficiency impairs endocytosis by stalling the actin-dependent invagination of endocytic clathrin-coated pits. Elife 3:e03311
Idevall-Hagren, Olof; Decamilli, Pietro (2014) Manipulation of plasma membrane phosphoinositides using photoinduced protein-protein interactions. Methods Mol Biol 1148:109-28
Demmel, Lars; Schmidt, Katy; Lucast, Louise et al. (2014) The endocytic activity of the flagellar pocket in Trypanosoma brucei is regulated by an adjacent phosphatidylinositol phosphate kinase. J Cell Sci 127:2351-64
Fröhlich, Florian; Christiano, Romain; Olson, Daniel K et al. (2014) A role for eisosomes in maintenance of plasma membrane phosphoinositide levels. Mol Biol Cell 25:2797-806
Schauder, Curtis M; Wu, Xudong; Saheki, Yasunori et al. (2014) Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer. Nature 510:552-5
Pirruccello, Michelle; Nandez, Ramiro; Idevall-Hagren, Olof et al. (2014) Identification of inhibitors of inositol 5-phosphatases through multiple screening strategies. ACS Chem Biol 9:1359-68
Tian, Xuefei; Kim, Jin Ju; Monkley, Susan M et al. (2014) Podocyte-associated talin1 is critical for glomerular filtration barrier maintenance. J Clin Invest 124:1098-113
Nández, Ramiro; Balkin, Daniel M; Messa, Mirko et al. (2014) A role of OCRL in clathrin-coated pit dynamics and uncoating revealed by studies of Lowe syndrome cells. Elife 3:e02975
Giordano, Francesca; Saheki, Yasunori; Idevall-Hagren, Olof et al. (2013) PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153:1494-509
Devereaux, Kelly; Dall'Armi, Claudia; Alcazar-Roman, Abel et al. (2013) Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS One 8:e76405

Showing the most recent 10 out of 16 publications