The major goal of this grant is to define defects in the phosphatidylinositol signaling pathway that result in human diseases. The role of inositol (1,3,4)-P3 5/6-kinase in inhibition of TNF-induced apoptosis will be investigated. Is the effect due to some inositol phosphate product or to phosphorylation of a protein of the apoptotic pathway? Mutant forms of recombinant kinase that lack either inositol or protein kinase activity will be created and tested for their ability to block TNF apoptosis. The enzymes leading to inositol hexaphosphate will be overexpressed in 293 cells or inhibited by RNAi to elucidate functions for the higher inositol phosphates in apoptosis, nuclear export of mRNA, and intracellular vesicle trafficking. The role of the B. pseudomallei protein BobB in virulence of this organism will be studied by determining whether it is an inositol phosphate phosphatase. The substrate specificity of two human homologues of BopB will be determined by cloning cDNA's encoding these proteins and producing recombinant protein in Sf9 cells. Continued studies of the myotubularin gene family (mutations of which cause several different human diseases) will be performed by investigating complexes between myotubularin related proteins 6 and 7 that are enzymatically active with the inactive myotubularin related protein 9. The role of complex formation in the pathogenesis of Lowe syndrome will be studied by determining the function of the inositol polyphosphate 5-phosphatase (OCRL) that is mutated in that disease. The role of OCRL in Golgi vesicle trafficking will be studied and the effect of mutated OCRL on the processing and/or activity of the NBC1 bicarbonate transporter of renal proximal tubules will be investigated. Malfunction of this transporter is suggested by the finding that mutations in NBC1 in humans produce a phenocopy of Lowe syndrome

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016634-42
Application #
7217272
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
1979-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
42
Fiscal Year
2007
Total Cost
$687,126
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhang, Chunfen; Majerus, Philip W; Wilson, Monita P (2012) Regulation of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) by reversible lysine acetylation. Proc Natl Acad Sci U S A 109:2290-5
Zou, Jun; Zhang, Chunfen; Marjanovic, Jasna et al. (2012) Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. Proc Natl Acad Sci U S A 109:9539-44
Zou, Jun; Majerus, Philip W; Wilson, David B et al. (2012) The role of myotubularin-related phosphatases in the control of autophagy and programmed cell death. Adv Biol Regul 52:282-9
Ferron, Mathieu; Boudiffa, Maya; Arsenault, Michel et al. (2011) Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab 14:466-77
Marjanovic, Jasna; Wilson, Monita P; Zhang, Chunfen et al. (2011) The role of inositol polyphosphate 4-phosphatase 1 in platelet function using a weeble mouse model. Adv Enzyme Regul 51:101-5
Majerus, Philip W; Wilson, David B; Zhang, Chunfen et al. (2010) Expression of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) and its role in neural tube defects. Adv Enzyme Regul 50:365-72
Traynor-Kaplan, Alexis E; Moody, Mark; Nur, Magda et al. (2010) INO-4995 therapeutic efficacy is enhanced with repeat dosing in cystic fibrosis knockout mice and human epithelia. Am J Respir Cell Mol Biol 42:105-12
Wilson, Monita P; Hugge, Christopher; Bielinska, Malgorzata et al. (2009) Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5/6-kinase. Proc Natl Acad Sci U S A 106:9831-5
Vomund, Anthony N; Majerus, Elaine M (2009) ADAMTS13 bound to endothelial cells exhibits enhanced cleavage of von Willebrand factor. J Biol Chem 284:30925-32
Jacoby, Monique; Cox, James J; Gayral, St├ęphanie et al. (2009) INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 41:1027-31

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