This project aims to define the roles of inositol signaling reactions in the pathogenesis of disease. We will study the role of inositol 1,3,4-5/6-kinase in fat cell differentiation. This enzyme catalyzes the first step in formation of inositol hexakisphosphate (IP6) which is essential for life in mammals. Preliminary studies indicate that the enzyme and others leading to IP6 production are highly expressed during fat cell differentiation and that some metabolite in this pathway may actually cause fat cell development. We will use overexpression and RNAi studies to define the causal molecule. In another study we plan to determine the potentially prothrombotic phenotype of mice with elevated levels of PI(3,4)P2. We propose that the elevated levels arise from deficiency of 4-ptaseI that occur in Weeble mutant mice. We have made radiation chimeric mice from lethally irradiated normal mice rescued by fetal liver transplants from Weeble embryos. Thus the Weeble mutation is restricted to blood cells and preliminary experiments suggest that these animals have a thrombotic phenotype. We will study platelet function and in vivo thrombosis in a laser injury model. We will investigate the functions of a little studied sub branch of the myotubularin PI 3-ptase family namely MTMR6, MTMR7, MTMR8 and their inactive partner MTMR9. These proteins play undefined roles in stress-induced apoptosis. We recently learned that mutations in another enzyme discovered in our lab are the cause of a severe neurodegeneration Jobert syndrome. The enzyme is inositol polyphosphate 5-phosphataseIV a lipid specific 5-PtaseIV. Dr Jos Gleeson (UCSD/HHMI) has found 5 different mutations in families with Joubert syndrome and has sent us cells and constructs to define the biological consequences of these mutations. In summary we use inositol biochemistry to determine the phenotype vs genotype of disorders of inositol metabolism.

Public Health Relevance

Our work has great health implications. It may lead to a prevention of folate resistant neural tube defects, a greater understanding of fat cell development, and find new reactions in platelet function that lead to heart attack and stroke. Analysis of mutations in patients with Joubert syndrome may bring understanding of this severe neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016634-45
Application #
7860438
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
45
Fiscal Year
2010
Total Cost
$1,144,086
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
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
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
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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